Multiplex imaging systems, devices, methods, and compositions including ferromagnetic structures

ABSTRACT

Multiplex imaging systems, devices, methods, and compositions are provided. A nuclear magnetic resonance imaging composition includes, but is not limited to, a plurality of ferromagnetic microstructures configured to generate a time-invariant magnetic field within at least a portion of one or more internal surface-defined voids.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is related to and claims the benefit of theearliest available effective filing dates from the following listedapplications (the “Related Applications”) (e.g., claims earliestavailable priority dates for other than provisional patent applicationsor claims benefits under 35 U.S.C. §116(e) for provisional patentapplications, for any and all parent, grandparent, great-grandparent,etc. applications of the Related Applications). All subject matter ofthe Related Applications and of any and all parent, grandparent,great-grandparent, etc. applications of the Related Applications isincorporated herein by reference to the extent such subject matter isnot inconsistent herewith.

RELATED APPLICATIONS

The present application is related to U.S. Patent Application No. to beassigned, entitled SYSTEM, DEVICES, METHODS, AND COMPOSITIONS INCLUDINGFERROMAGNETIC STRUCTURES, naming Roderick A. Hyde, Jordin T. Kare, andWayne R. Kindsvogel as inventors, filed 29, May, 2009, which is DocketNo. 0508-004-008-000000.

The present application is related to U.S. Patent Application No. to beassigned, entitled SYSTEM, DEVICES, METHODS, AND COMPOSITIONS INCLUDINGTARGETED FERROMAGNETIC STRUCTURES, naming Roderick A. Hyde, Jordin T.Kare, and Wayne R. Kindsvogel as inventors, filed 29, May, 2009, whichis Docket No. 0508-004-018-000000.

The present application is related to U.S. Patent Application No. to beassigned, entitled SYSTEM, DEVICES, METHODS, AND COMPOSITIONS INCLUDINGSELECTIVELY ACCESSIBLE FERROMAGNETIC STRUCTURES, naming Roderick A.Hyde, Jordin T. Kare, and Wayne R. Kindsvogel as inventors, filed 29,May, 2009, which is Docket No. 0508-004-019-000000.

The present application is related to U.S. Patent Application No. to beassigned, entitled NON-EXTERNAL STATIC MAGNETIC FIELD IMAGING SYSTEMS,DEVICES, METHODS, AND COMPOSITIONS, naming Roderick A. Hyde, Jordin T.Kare, and Wayne R. Kindsvogel as inventors, filed 29, May, 2009, whichis Docket No. 0508-004-020-000000.

The present application is related to U.S. Patent Application No. to beassigned, entitled SYSTEMS, DEVICES, METHODS, AND COMPOSITIONS INCLUDINGFUNCTIONALIZED FERROMAGNETIC MICROSTRUCTURES, naming Roderick A. Hyde,Jordin T. Kare, and Wayne R. Kindsvogel as inventors, filed 29, May,2009, which is Docket No. 0508-004-022-000000.

SUMMARY

In an aspect, the present disclosure is directed to, among other things,a method for obtaining a non-external magnetic field resonance image ofa region within a biological subject. The method includes, but is notlimited to, detecting (e.g., assessing, calculating, evaluating,determining, gauging, measuring, monitoring, quantifying, resolving,sensing, or the like) a spatial distribution of a magnetic resonanceevent (e.g., nuclear magnetic information, RF information, an RF signal,a nuclear magnetic resonance, an in vivo magnetic resonance event, orthe like) associated with one or more net nuclear spin isotopes exposedto a plurality of target-selective microstructures configured togenerate a static magnetic field within one or more surface-definedvoids and to affect a magnetic resonance relaxation process associatedwith the net nuclear spin isotopes interrogated by the generated staticmagnetic field.

In an aspect, the present disclosure is directed to, among other things,a nuclear magnetic resonance imaging composition. The nuclear magneticresonance imaging composition includes, but is not limited to, aplurality of ferromagnetic microstructures. In an embodiment, one ormore of the plurality of ferromagnetic microstructures include, but arenot limited to, a first internal surface defining a void that isaccessible to a biological sample. In an embodiment, one or more of theplurality of ferromagnetic microstructures are configured to generate atime-invariant magnetic field within at least a portion of the void. Inan embodiment, at least one of the plurality of ferromagneticmicrostructures includes one or more targeting moieties attached thereof

In an aspect, the present disclosure is directed to, among other things,a composition. The composition includes, but is not limited to, one ormore selectively-accessible ferromagnetic microstructures, at least oneof the one or more selectively-accessible ferromagnetic microstructuresincluding at least a first internal surface defining a void. In anembodiment, the void is configured to be selectively-accessible to abiological sample. In an embodiment, at least one of the one or moreselectively-accessible ferromagnetic microstructures includes asufficient amount of one or more ferromagnetic materials to generate atime-invariant magnetic field within the void.

In an aspect, the present disclosure is directed to, among other things,an imaging system. The imaging system includes, but is not limited to, aplurality of ferromagnetic microstructures. In an embodiment, one ormore of the plurality of ferromagnetic microstructures include, but arenot limited to, a first internal surface defining one or more voids. Inan embodiment, at least one of the one or more voids is configured to beaccessible to a biological sample. In an embodiment, one or more of theplurality of ferromagnetic microstructures include a sufficient amountof one or more ferromagnetic materials to generate a time-invariantmagnetic field within at least a portion of at least one of the one ormore voids.

In an aspect, the present disclosure is directed to, among other things,a nuclear magnetic resonance imaging system. The nuclear magneticresonance imaging system includes, but is not limited to, a plurality offerromagnetic microstructures. In an embodiment, one or more of theplurality of ferromagnetic microstructures include, but are not limitedto, a first internal surface defining a void configured to beselectively-accessible to a biological sample. In an embodiment, one ormore of the plurality of ferromagnetic microstructures include, but arenot limited to, a sufficient amount of one or more ferromagneticmaterials to generate a time-invariant magnetic field within the void.

In an aspect, the present disclosure is directed to, among other things,a system. The system includes, but is not limited to, circuitry foracquiring information associated with an in vivo magnetic resonanceevent generated by nuclear magnetic resonance detectable nuclei receivedin one or more voids of a plurality of ferromagnetic microstructuresconfigured to generate a static magnetic field within the void. Thesystem can include, but is not limited to, circuitry for generating aresponse based on acquired information. In an embodiment, the system caninclude, but is not limited to, circuitry for communicating thegenerated response to a user. In an embodiment, the system can include,but is not limited to, circuitry for generating a radio frequencymagnetic field of a character and for a sufficient time to excite atleast some of the nuclear magnetic resonance detectable nuclei receivedin one or more voids of the plurality of ferromagnetic microstructures.

In an aspect, the present disclosure is directed to, among other things,an apparatus. The apparatus includes, but is not limited to, means foraffecting an in vivo magnetic resonance relaxation process associatedwith a biological sample, in the absence of an externally generatedmagnetic field. The apparatus can include, but is not limited to, meansfor acquiring at least one spatial distribution parameter of a magneticresonance event associated with the affected in vivo magnetic resonancerelaxation process. The apparatus can include, but is not limited to,means for generating a response based on at least one acquired spatialdistribution parameter.

In an aspect, the present disclosure is directed to, among other things,a computer program product including signal-bearing media containingcomputer instructions which, when run on a computing device, cause thecomputing device to implement a method including detecting a spatialdistribution of a magnetic resonance event associated with a biologicalsample exposed to a surface-defined void of a ferromagneticmicrostructure configured to generate a static magnetic field within thesurface-defined void and configured to affect a magnetic resonancerelaxation process associated with the biological sample at least whilethe biological sample is received in the surface-defined void. In anembodiment, the computer program product includes signal-bearing mediacontaining computer instructions which, when run on a computing device,cause the computing device to implement a method including, but notlimited to, generating a response based on the detected spatialdistribution of the magnetic resonance event. In an embodiment, thecomputer program product includes signal-bearing media containingcomputer instructions which, when run on a computing device, cause thecomputing device to implement a method including, but not limited to,communicating the response to a user.

In an aspect, the present disclosure is directed to, among other things,a method for obtaining magnetic resonance information (e.g., spectralinformation, an image, a spectrum, a magnetic resonance scan, RFinformation, or the like) of a region within a biological subjectwithout the need or use of an external-magnet. The method includes, butis not limited to, detecting a spatial distribution of a magneticresonance event associated with a targeted biological sample exposed toa surface-defined void of a ferromagnetic microstructure configured togenerate a static magnetic field within the surface-defined void andconfigured to affect a magnetic resonance relaxation process associatedwith the biological sample at least while the biological sample isreceived in the surface-defined void. The method can include, but is notlimited to, generating a response based on the detected spatialdistribution of the magnetic resonance event.

In an aspect, the present disclosure is directed to, among other things,a method for obtaining a non-external magnetic field resonance image ofa region within a biological subject. The method includes, but is notlimited to, detecting a spatial distribution of a magnetic resonanceevent associated with one or more nuclear magnetic resonance detectablenuclei exposed to a plurality of target-selective microstructures. In anembodiment, at least a portion of the plurality of target-selectivemicrostructures includes, but is not limited to, one or moresurface-defined voids. In an embodiment, at least a portion of theplurality of target-selective microstructures is configured to generatea static magnetic field within the one or more surface-defined voids andconfigured to affect a magnetic resonance relaxation process associatedwith the nuclear magnetic resonance detectable nuclei exposed to thegenerated static magnetic field. The method can include, but is notlimited to, providing a response based on the detected spatialdistribution of the magnetic resonance event.

In an aspect, a method includes, but is not limited to, detectingregional information associated with a magnetic resonance eventgenerated by in vivo target tissue-contained non-zero spin nuclei (e.g.,nuclei having spin quantum number I>0, spin-half particles, spin ½nuclei, ¹H (I=½), ²H (I=1), ¹³C (I=½), ¹⁹F (I=½), ³¹P (I=½), ²³Na(I=3/2), or the like) exposed to one or more voids of a plurality offerromagnetic microstructures configured to generate a static magneticflux density within the void. The method can include, but is not limitedto, generating a response based on the detected regional information.

In an aspect, the present disclosure is directed to, among other things,a method for obtaining magnetic resonance information of a region withina biological subject in absence of an externally generated magneticfield (other than the Earth's magnetic field) (e.g., a strong externalmagnetic field, a static magnetic field, or the like). The methodincludes, but is not limited to, monitoring a magnetic resonance eventgenerated by net nuclear spin isotopes present in a biological samplereceived in a void of a ferromagnetic microstructure configured togenerate a static magnetic field within the void. The method caninclude, but is not limited to, providing a response based on themonitored magnetic resonance event.

In an aspect, a method includes, but is not limited to, affecting atleast one of a non-zero spin nuclei transverse magnetic relaxation timeor a non-zero spin nuclei longitudinal magnetic relaxation timeassociated with a biological sample by providing a plurality offerromagnetic microstructures to at least a portion of the biologicalsample, at least some of the plurality of ferromagnetic microstructuresincluding a first internal surface defining a void selectivelyaccessible to the biological sample. In an embodiment, the plurality offerromagnetic microstructures include a sufficient amount of at leastone ferromagnetic material to generate a time-invariant magnetic fieldwithin the void. In an embodiment, the time-invariant magnetic field isof a sufficient character to affect at least one of a non-zero spinnuclei transverse magnetic relaxation time or a non-zero spin nucleilongitudinal magnetic relaxation time associated with the biologicalsample.

In an aspect, the present disclosure is directed to, among other things,a multiplex nuclear magnetic resonance imaging composition. Themultiplex nuclear magnetic resonance imaging composition includes, butis not limited to, a plurality of ferromagnetic microstructure sets. Inan embodiment, each ferromagnetic microstructure set includes, but isnot limited to, one or more ferromagnetic microstructures including anaccessible internal void. In an embodiment, one or more of theferromagnetic microstructures are configured to generate acharacteristic time-invariant magnetic field within the accessibleinternal void. In an embodiment, at least one of the ferromagneticmicrostructure sets includes, but is not limited to, a differentcharacteristic time-invariant magnetic field from another of theferromagnetic microstructure sets.

In an aspect, the present disclosure is directed to, among other things,a multiplex imaging method. The multiplex imaging method includes, butis not limited to, affecting at least one of a non-zero spin nucleitransverse magnetic relaxation time (e.g., a proton transverse magneticrelaxation time) or a non-zero spin nuclei longitudinal magneticrelaxation time (e.g., a proton longitudinal magnetic relaxation time)associated with a biological sample by providing a plurality offerromagnetic microstructure sets. In an embodiment, each ferromagneticmicrostructure set includes one or more ferromagnetic microstructuresconfigured to include an accessible internal void and configured togenerate a characteristic time-invariant magnetic field within theaccessible internal void. In an embodiment, at least one of theferromagnetic microstructure sets includes a different characteristictime-invariant magnetic field from another of the ferromagneticmicrostructure sets.

In an aspect, the present disclosure is directed to, among other things,a method of multiplex interrogation of a biological sample. The methodincludes, but is not limited to, detecting nuclear magnetic resonanceinformation generated by in vivo nuclear magnetic resonance detectablenuclei exposed to one or more internal-surface-defined voids of aplurality of different ferromagnetic microstructures. In an embodiment,the plurality of different ferromagnetic microstructures are configuredto generate a static magnetic flux density within at least a portion ofthe one or more internal-surface-defined voids and configured to affecta magnetic resonance relaxation process associated with the in vivonuclear magnetic resonance detectable nuclei while the in vivo nuclearmagnetic resonance detectable nuclei are received in at least one of theone or more internal-surface-defined voids.

In an aspect, a method includes, but is not limited to, detecting amagnetic resonance event associated with one or more nuclear magneticresonance detectable nuclei exposed to a static magnetic field withinone or more surface-defined voids of a plurality of target-selectivemicrostructures. In an embodiment, detecting the magnetic resonanceevent includes associated detecting the magnetic resonance informationassociated with one or more nuclear magnetic resonance detectable nucleiexposed to a static magnetic field within one or moreselectively-accessible voids of a plurality of target-selectivemicrostructures.

In an aspect, the present disclosure is directed to, among other things,an imaging system. The imaging system includes, but is not limited to, aplurality of ferromagnetic microstructures. In an embodiment, one ormore of the plurality of ferromagnetic microstructures are configure toinclude an external surface and an internal surface defining a void. Inan embodiment, one or more of the plurality of ferromagneticmicrostructures are configured to generate a time-invariant magneticfield within at least a portion of the void. In an embodiment, the voidis accessible to a biological sample. In an embodiment, at least one ofthe external surface or the internal surface is configured to includeone or more functional groups. In an embodiment, at least one of theexternal surface or the internal surface is configured to include one ormore of a bio-compatible functional group, a charge functional group, achemically reactive functional group, a hydrophilic functional group, ahydrophobic functional group, or an organofunctional group. In anembodiment, the external surface includes a bio-compatible functionalgroup, a charge functional group, a chemically reactive functionalgroup, a hydrophilic functional group, a hydrophobic functional group,or an organofunctional group, and the internal surface includes adifferent one of a bio-compatible functional group, a charge functionalgroup, a chemically reactive functional group, a hydrophilic functionalgroup, a hydrophobic functional group, or an organofunctional group. Theimaging system can include, but is not limited to, a radio frequencytransmitter configured to generate a radio frequency signal. The imagingsystem can include, but is not limited to, one or more coils configuredto generate one or more radio frequency pulses. The imaging system caninclude, but is not limited to, means for acquiring at least one spatialdistribution parameter of a magnetic resonance event associated with oneor more non-zero spin nuclei of a biological sample present within thevoid. In an embodiment, the imaging system includes a radio frequencyreceiver configured to acquire radio frequency information emitted bythe biological sample.

In an aspect, a method includes, but is not limited to, detecting aspatial distribution of a magnetic resonance event associated with atargeted biological sample exposed to a surface-defined void of one ormore selectively-targeted ferromagnetic microstructures configured togenerate a static magnetic field within the surface-defined void andconfigured to affect a magnetic resonance relaxation process associatedwith the biological sample at least while the biological sample isreceived in the surface-defined void. In an embodiment, detecting thespatial distribution of a magnetic resonance event associated with atargeted biological sample exposed to a surface-defined void of one ormore selectively-targeted ferromagnetic microstructures includesdetecting the spatial distribution of the magnetic resonance eventassociated with one or more ferromagnetic microstructuresselectively-targeted to at least one cell surface receptor targetingmoiety. In an embodiment, detecting the spatial distribution of amagnetic resonance event associated with a targeted biological sampleexposed to a surface-defined void of one or more selectively-targetedferromagnetic microstructures includes detecting the spatialdistribution of the magnetic resonance event associated with one or moreselectively-targeted ferromagnetic microstructures including at leastone of a transmembrane receptor targeting moiety, an antigen-targetingmoiety, an immune-receptor targeting moiety, a folate receptor targetingmoiety, a nucleotide binding moiety, an oligonucleotide binding moiety,an oligodeoxyribonucleotide binding moiety, an oligoribonucleotidebinding moiety. In an embodiment, detecting a spatial distribution of amagnetic resonance event associated with a targeted biological sampleexposed to a surface-defined void of one or more selectively-targetedferromagnetic microstructures includes detecting the spatialdistribution of the magnetic resonance event associated with one or moreselectively-targeted ferromagnetic microstructures including at leastone of an amyloid binding moiety or a β-amyloid binding moiety. In anembodiment, detecting a spatial distribution of a magnetic resonanceevent associated with a targeted biological sample exposed to asurface-defined void of one or more selectively-targeted ferromagneticmicrostructures includes detecting the spatial distribution of themagnetic resonance event associated with one or more ferromagneticmicrostructures selectively-targeted to one or more genomic targets. Themethod may further include generating a response based on the detectedspatial distribution of the magnetic resonance event.

The foregoing summary is illustrative only and is not intended to be inany way limiting. In addition to the illustrative aspects, embodiments,and features described above, further aspects, embodiments, and featureswill become apparent by reference to the drawings and the followingdetailed description.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1A-1G are perspective views of ferromagnetic microstructuresaccording to multiple illustrated embodiments.

FIG. 2 is a perspective view of a plurality of ferromagneticmicrostructures according to one illustrated embodiment.

FIGS. 3A, 3B, and 3C are perspective views of pluralities offerromagnetic microstructures according to multiple illustratedembodiments.

FIG. 4 is a schematic diagram of a system including a pluralities offerromagnetic microstructures according to one illustrated embodiment.

FIGS. 5A and 5B are flow diagrams of a method according to oneillustrated embodiment.

FIGS. 6A, 6B, and 6C are flow diagrams of a method according to oneillustrated embodiment.

FIG. 7 is a flow diagram of a method according to one illustratedembodiment.

FIG. 8 is a flow diagram of a method according to one illustratedembodiment.

FIG. 9 is a flow diagram of a method according to one illustratedembodiment.

FIG. 10 is a flow diagram of a method according to one illustratedembodiment.

FIG. 11 is a flow diagram of a method according to one illustratedembodiment.

FIG. 12 is a flow diagram of a method according to one illustratedembodiment.

FIG. 13 is a flow diagram of a method according to one illustratedembodiment.

FIG. 14 is a flow diagram of a method according to one illustratedembodiment.

FIGS. 15A-15D are flow diagrams of a method according to one illustratedembodiment.

FIG. 16 is a flow diagram of a method according to one illustratedembodiment.

FIGS. 17A-17R are flow diagrams of a method according to one illustratedembodiment.

DETAILED DESCRIPTION

In the following detailed description, reference is made to theaccompanying drawings, which form a part hereof. In the drawings,similar symbols typically identify similar components, unless contextdictates otherwise. The illustrative embodiments described in thedetailed description, drawings, and claims are not meant to be limiting.Other embodiments may be utilized, and other changes may be made,without departing from the spirit or scope of the subject matterpresented here.

Nuclear Magnetic Resonance (NMR) is a quantum mechanical phenomenon inwhich a system of spins (e.g., non-zero spin nuclei, or the like) placedin a static magnetic field H ₀ resonantly absorbs energy applied at acertain electromagnetic frequency. In the presence of the staticmagnetic field, the non-zero spin nuclei precess about the magneticfield's axis at an angular frequency ω₀. See, e.g., Shankar R.,Principles of Quantum Mechanics, 2nd edition, Plenum (1994). Ifinterrogated with a short, precisely-tuned burst of radio frequencywaves, the non-zero spin nuclei will momentarily precess off axis and,in the process of returning to their original orientation, will resoundwith a brief radio frequency signal of their own. See, e.g., U.S.Department of Energy, Magnetic Resonance Imager: Project Fact Sheet(Jan. 13, 2003). The time constant associated with the elapsed time forthe spin system to return to thermal equilibrium along the staticmagnetic field's axis is known as “longitudinal relaxation time” or“spin-lattice relaxation time,” often denoted as T₁. An additional timeconstant associated with the elapsed time in which the transversemagnetization diminishes by the principle of maximal entropy is known as“spin-spin relaxation time” or “transverse relaxation time,” oftendenoted as T₂. NMR (e.g., magnetic resonance imaging, or the like) andother spectroscopy techniques and methodologies exploit these phenomenato obtaining information regarding, for example, chemical and physicalmicroscopic properties of a sample or biological subject. A moredetailed discussion of magnetic resonance may be found in, for example,the following documents (the contents of which are incorporated hereinby reference): C. P. Slichter, Principles of Magnetic Resonance, 3^(rd)ed., Springer-Verlag, Berlin, pp. 1-63 (1990); J. D. Roberts, NuclearMagnetic Resonance, McGraw-Hill, New York, pp. 1-19 (1959)Cohen-Tannoudji et al., Quantum Mechanics, Vol. 1, New York, N.Y.: Wiley(1977); WO 2009/027973 (published Mar. 5, 2009), WO 2009/029880(published Mar. 5, 2009), and WO 2009/029896 (published Mar. 5, 2009).

Often, a sample or biological subject is placed in the bore or within aninterior of an external magnet (e.g., a permanent magnet, resistivemagnet, a superconducting magnet, or the like) that generates the staticmagnetic field H ₀. For example, conventional MRI employs, among otherthings, an external primary or main magnet (for generating a staticmagnetic field H ₀), as well as magnetic field gradient coils and radiofrequency coils, to produce detailed images of organs, soft tissues,bone, and other internal body structures. See, e.g., U.S. Pat. No.7,495,439 (issued Feb. 24, 2009) (the contents of which is incorporatedherein by reference).

As a non-limiting example, certain systems, devices, methods, andcompositions described herein provide for the detection of regionalinformation associated with a magnetic resonance event generated by, forexample, in vivo target non-zero spin nuclei without the use or need ofan external (ex vivo) magnet (e.g., a permanent magnet, resistivemagnet, a superconducting magnet, or the like). An aspect includessystems, devices, methods, and compositions for obtaining magneticresonance information of one or more regions within a biological subjectin absence of an externally generated static magnetic field. An aspectincludes systems, devices, methods, and compositions for imaging atleast one of a T₁ magnetic relaxation time or a T₂ magnetic relaxationtime associated with in vivo non-zero spin nuclei.

An aspect includes non-external magnetic field imaging systems, devices,methods, and compositions. A non-limiting approach includes systems,devices, methods, and compositions for obtaining a non-external magneticfield resonance image of a region within a biological subject

An aspect includes systems, devices, and methods employing compositionsincluding, among other things, one or more ferromagneticmicrostructures. A non-limiting approach includes nuclear magneticresonance imaging systems, devices, and methods including, among otherthings, compositions having a plurality of ferromagnetic microstructuresets. A non-limiting approach includes systems, devices, and methodsincluding, among other things, one or more ferromagnetic contrast agentcompositions. A non-limiting approach includes systems, devices, andmethods including a nuclear magnetic resonance imaging compositionhaving a plurality of ferromagnetic microstructures.

Referring to FIGS. 1A through 1G, in an embodiment, a nuclear magneticresonance imaging composition includes, but is not limited to, one ormore ferromagnetic microstructures 102. In an embodiment, one or more ofthe ferromagnetic microstructures 102 include, but are not limited to,at least a first internal surface 104 defining a void 106 accessible toa biological sample. In an embodiment, one or more of the ferromagneticmicrostructures 102 include at least an outer surface 110. In anembodiment, one or more of the ferromagnetic microstructures 102 areconfigured to generate one or more time-invariant magnetic fields 108within at least a portion of the void 106. In an embodiment, thetime-invariant magnetic field 108 within the void 106 includes asubstantially homogeneous polarizing magnetic field region.

In an embodiment, at least one of the ferromagnetic microstructures 102includes one or voids 106. The at least a first internal surface 104 candefining one or voids 106 having any geometric form including regular orirregular forms and may have a cross-section of substantially any shapeincluding, but not limited to, circular, triangular, square, rectangularpolygonal, regular or irregular shapes, or the like, as well as othersymmetrical and asymmetrical shapes, or combinations thereof.

In an embodiment, a plurality of ferromagnetic microstructures includestwo or more of the ferromagnetic microstructures 102. In an embodiment,the plurality of ferromagnetic microstructures include one or moredifferent time-invariant magnetic field 108 strengths. In an embodiment,one or more of the ferromagnetic microstructures 102 are configured toinclude one or more different void 106 dimensions. In an embodiment, theplurality of ferromagnetic microstructures include at least a firstplurality of ferromagnetic microstructures 102 sized and dimensioned togenerate a first magnetic flux density within the void 106 and a secondplurality of ferromagnetic microstructures 102 sized and dimensioned togenerate a second magnetic flux density within the void 106, the secondmagnetic flux density different from the first magnetic flux density.

In an embodiment, the plurality of ferromagnetic microstructures includeat least a first plurality of ferromagnetic microstructures 102configured to generate a time-invariant magnetic field 108 within thevoid 106 of a first magnetic field strength and a second plurality offerromagnetic microstructures configured to generate a time-invariantmagnetic field 108 within the void 106 of a second magnetic fieldstrength, the second magnetic field strength different from the firstmagnetic field strength. In an embodiment, the plurality offerromagnetic microstructures include at least a first plurality offerromagnetic microstructures 102 configured to generate atime-invariant magnetic field 108 within the void 106 of a firstmagnetic field spatial distribution and a second plurality offerromagnetic microstructures configured to generate a time-invariantmagnetic field 108 within the void 106 of a second magnetic fieldspatial distribution, the second magnetic field spatial distributiondifferent from the first magnetic field spatial distribution.

In an embodiment, the composition includes a plurality of ferromagneticmicrostructures 102 including at least a first plurality offerromagnetic microstructures sized and dimensioned to generate atime-invariant magnetic field 108 within the void 106 of a firstmagnetic field strength and a second plurality of ferromagneticmicrostructures sized and dimensioned to generate a time-invariantmagnetic field 108 within the void 106 of a second magnetic fieldstrength. In an embodiment, the second magnetic field strength isdifferent from the first magnetic field strength.

An aspect includes systems, devices, methods, and compositionsincluding, among other things, microstructures including ferromagneticmaterials. In an embodiment, one or more of the microstructures includeone or more ferromagnetic materials.

Ferromagnetic materials include those materials having a Curietemperature, above which thermal agitation destroys the magneticcoupling giving rise to the alignment of the elementary magnets(electron spins) of adjacent atoms in a lattice (e.g., a crystallattice). In an embodiment, one or more of the ferromagneticmicrostructures 102 include one or more ferromagnets. Amongferromagnetic materials, examples include, but are not limited to,crystalline ferromagnetic materials, ferromagnetic oxides, materialshaving a net magnetic moment, materials having a positive susceptibilityto an external magnetic field, non-conductive ferromagnetic materials,non-conductive ferromagnetic oxides, ferromagnetic elements (e.g.,cobalt, gadolinium, iron, or the like), rare earth elements,ferromagnetic metals, ferromagnetic transition metals, materials thatexhibit magnetic hysteresis, and the like, and alloys or mixturesthereof.

Further examples of ferromagnetic materials include, but are not limitedto, chromium (Cr), cobalt (Co), copper (Cu), dysprosium (Dy), europium(Eu), gadolinium (Gd), iron (Fe), magnesium (Mg), neodymium (Nd), nickel(Ni), yttrium (Y), and the like. Further examples of ferromagneticmaterials include, but are not limited to, chromium dioxide (CrO₂),copper ferrite (CuOFe₂O₃), europium oxide (EuO), iron(II, III) oxide(FeOFe₂O₃), iron(III) oxide (Fe₂O₃), magnesium ferrite (MgOFe₂O₃),manganese ferrite (MnOFe₂O₃), nickel ferrite (NiOFe₂O₃),yttrium-iron-garnet (Y₃Fe₅O₁₂), and the like. Further examples offerromagnetic materials include, but are not limited to, manganesearsenide (MnAs), manganese bismuth (MnBi), manganese(III) antimonide(MnSb), Mn—Zn ferrite, neodymium alloys, neodymium, Ni—Zn ferrite, andsamarium-cobalt.

In an embodiment, one or more of the ferromagnetic microstructures 102include at least one iron oxide. Among iron oxides, examples include,but are not limited to, copper ferrite (CuOFe₂O₃), iron(II, III) oxide(FeOFe₂O₃), iron(III) oxide (Fe₂O₃), magnesium ferrite (MgOFe₂O₃),manganese ferrite (MnOFe₂O₃), nickel ferrite (NiOFe₂O₃),yttrium-iron-garnet (Y₃Fe₅O₁₂), ferric oxides, ferrous oxides, and thelike. In an embodiment, one or more of the ferromagnetic microstructures102 are configured to include one or more magnetic components.

In an embodiment, one or more of the ferromagnetic microstructures 102include at least one electrically non-conductive ferromagnetic material.Among electrically non-conductive ferromagnetic materials, examplesinclude, but are not limited to, ceramic magnets, ferrite, and the like.In an embodiment, one or more of the ferromagnetic microstructures 102include at least one electrically non-conductive ferromagnetic oxide orferrimagnetic oxide. In an embodiment, one or more of the ferromagneticmicrostructures 102 include at least one electrically non-conductiveferromagnetic ceramic material or ferrimagnetic ceramic material.

In an embodiment, one or more of the ferromagnetic microstructures 102include at least one ferromagnetic oxide. Among ferromagnetic oxides,examples include, but are not limited to, three main groups of ferrites:spinels, garnets, and magnetoplumbites. Spinels have the general formulaMOFe₂O₃, MFe₂O₄, or MFe₃O₄ where M represents nickel (Ni), zinc (Zn),manganese (Mn), magnesium (Mg), lithium (Li), copper (Cu), cobalt (Co),iron (Fe) or other ion (e.g., divalent ions). Garnets have the generalformula 3M₂O₃.5Fe₂O₃ or M₃Fe₅O₁₂, where M is represents yttrium (Y) orone of the rare earth ions. Magnetoplumbites have the general formulaAM₁₂O₁₉ (e.g., BaFe₁₂O₁₉, SrFe₁₂O₁₉, or the like); (Pb, Mn)(Fe,Mn)₁₂O₁₉; MFe₁₂O₁₉ or MO.6Fe₂O₃; where M is barium (Ba), Strontium (Sr)lead (Pb), aluminum (Al), gallium (Ga), chromium (Cr) or manganese (Mn).These ferromagnetic oxides can also be combined in many ways dependingon a particular application. See, e.g., (the contents of which areincorporated herein by reference) U.S. Pat. No. 5,532,667 (issued Jul.2, 1996) and Goldman A, Modern Ferrite Technology, 2^(nd) Ed., SpringerScience & Business (2006).

Further examples of ferromagnetic oxides include rare earth iron garnetshaving the general formula of (3M₂O₃)C(2Fe₂O₃)A(3Fe₂O₃)D where M isyttria or rare earth ion and (A,C,D) are lattice site. Further examplesof ferromagnetic oxides include microwave or ferromagnetic garnets suchas, for example, yttrium aluminum iron garnet or YIG (Y₂Fe₅O₁₂). In anembodiment, magnetization levels of microwave or ferromagnetic garnetsare modified by substituting Al for Fe or combinations of Ho, Dy or Gdfor Y. Further examples of ferromagnetic oxides include, but are notlimited to, amorphous ferromagnetic oxides, ferromagnetic metal oxide,iron oxides, perovskite manganite, lanthanum strontium manganite, rareearth oxides, spinel ferrite, and the like. In an embodiment, one ormore of the ferromagnetic microstructures 102 include at least one ofchromium dioxide (CrO₂) or europium oxide (EuO).

In an embodiment, one or more of the ferromagnetic microstructures 102include at least one of chromium (Cr), cobalt (Co), copper (Cu),dysprosium (Dy), europium (Eu), gadolinium (Gd), iron (Fe), magnesium(Mg), neodymium (Nd) nickel (Ni), or yttrium (Y). In an embodiment, oneor more of the ferromagnetic microstructures 102 include at least one ofmanganese(III) antimonide (MnSb), manganese arsenide (MnAs), ormanganese bismuth (MnBi). In an embodiment, one or more of theferromagnetic microstructures 102 include at least one of Mn—Zn ferriteor Ni—Zn ferrite. In an embodiment, one or more of the ferromagneticmicrostructures 102 include one or more rare earth elements. In anembodiment, one or more of the ferromagnetic microstructures 102 includeat least one of neodymium, neodymium alloys, or samarium-cobalt.

An aspect includes systems, devices, methods, and compositionsincluding, among other things, microstructures including at least one ofa ferromagnetic material or a ferrimagnetic material. In an embodiment,one or more of the ferromagnetic microstructures 102 include at leastone ferrimagnetic material. In an embodiment, one or more of theferromagnetic microstructures 102 include one or more ferrimagnets(e.g., soft ferrites, hard ferrites, or the like). Among ferrimagneticmaterials, examples include, but are not limited to, ferrimagneticoxides (e.g., ferrites, garnets, or the like). Further examples offerrimagnetic materials include ferrites with a general chemical formulaof AB₂O₄ (e.g., CoFe₂O₄, MgFe₂O₄, ZnFe₂O₄) where A and B representvarious metal cations. In an embodiment, A is Mg, Zn, Mn, Ni, Co, orFe(II); B is Al, Cr(III), Mn(III) or Fe(III); and O is oxygen. In anembodiment, A is a divalent atom of radius ranging from about 80 pm toabout 110 pm (e.g., Cu, Fe, Mg, Mn, Zn, or the like), B is a trivalentatom of radius ranging from about 75 pm to about 90 pm, (e.g., Al, Fe,Co, Ti, or the like), and O is oxygen. Further examples of ferrimagneticmaterials include iron ferrites with a general chemical formula MOFe₂O₃(e.g., CoFe₂O₄, Fe₃O₄, Mge₂O₄, or the like) where M is a divalent ionsuch as Fe, Co, Cu, Li, Mg, Ni, or Zn. Further examples of ferromagneticmaterials include materials having a magnetization compensation point,materials that are associated with a partial cancellation ofantiferromagnetically aligned magnetic sublattices with different valuesof magnetic moments, or material having different temperaturedependencies of magnetization. See e.g., Kageyama et al., WeakFerrimagnetism, Compensation Point, and Magnetization Reversal inNi(HCOO)₂.2H₂O, Physical Rev. B, 224422 (2003).

An aspect includes imaging systems, devices, methods, and compositionsincluding, among other things, microstructure including one or moreradio frequency transparent materials. See, e.g., U.S. Pat. No.5,506,053 (issued Apr. 9, 1996) (the contents of which are incorporatedherein by reference). A non-limiting approach includes imaging systems,devices, methods, and compositions including, among other things,ferromagnetic microstructures 102 including one or more radio frequencyshielding materials. In an embodiment, one or more of the ferromagneticmicrostructures 102 include a sufficient amount of a layer, a mesh, aconductive structure, or a conductive coating to limit the penetrationof electromagnetic fields into a space within a ferromagneticmicrostructure 102, by blocking them with a barrier made of conductivematerial. In an embodiment, one or more of the ferromagneticmicrostructures 102 include a sufficient amount of a conductivematerial, and are configured, to redistribute electrical chargesassociated with an electrical field within the conducting material tocancel the electrical field's effects within the ferromagneticmicrostructures interior.

In an embodiment, one or more of the ferromagnetic microstructures 102include a sufficient amount of a high magnetic permeability metal alloysto draw the magnetic fields associated with the particular ferromagneticmicrostructure 102 into themselves, and provide a path for the magneticfield lines around a shielded ferromagnetic microstructure 102. In anembodiment, one or more of the ferromagnetic microstructures 102 areconfigured to limit an external self-generated magnetic field moment. Inan embodiment, one or more of the ferromagnetic microstructures 102 areconfigured to include a substantially U-shape magnetic structure (e.g.,a horseshoe shaped magnet, or the like) that is configured to confinethe magnetic field lines within a volumetric footprint occupied by theferromagnetic microstructure 102. In an embodiment, at least one of theferromagnetic microstructures 102 is configured to generate a constantmagnetic field confined within a volumetric footprint occupied by theferromagnetic microstructure 102. In an embodiment, one or more of theferromagnetic microstructures 102 are configured to confine a generatedmagnetic filed to a region located within the ferromagneticmicrostructure 102. In an embodiment, one or more of the ferromagneticmicrostructures 102 are configured to include one or more magneticstructures. In an embodiment, one or more of the ferromagneticmicrostructures 102 are configured limit an external self-generatedmagnetic field by including one or more magnetic structures forming amagnetic filed return path. In an embodiment, one or more of theferromagnetic microstructures 102 are configured to include one or moremagnetic dipoles. In an embodiment, one or more of the ferromagneticmicrostructures 102 are configured to limit an external self-generatedmagnetic field. In an embodiment, one or more of the ferromagneticmicrostructures 102 include one or more magnetic dipoles in aconfiguration that limits an external self-generated magnetic fieldassociated with a ferromagnetic microstructure 102. In an embodiment,one or more of the ferromagnetic microstructures 102 include one or moremagnetic dipoles in a configuration including unlike poles opposing eachother. In an embodiment, one or more of the ferromagneticmicrostructures 102 include a sufficient amount of a ferromagneticmaterial to generate one or more magnetic poles. In an embodiment, oneor more of the ferromagnetic microstructures 102 include a sufficientamount of a ferrimagnetic material to generate one or more magneticdipoles. In an embodiment, one or more of the ferromagneticmicrostructures 102 include a sufficient amount of a ferrimagneticmaterial to generate one or more magnets.

In an embodiment, one or more of the ferromagnetic microstructures 102include one or more conductive traces that are deposited, etched,sintered, or otherwise applied to a ferromagnetic microstructure 102 toform an electromagnetic shielding structure. For example, lithographictechniques can be use to form a conductive trace layout onto a surfaceof a ferromagnetic microstructure 102 or conductive trace layout onto alayer surrounding a ferromagnetic microstructure 102. The lithographicprocess for forming the conductive trace layouts can include forexample, but not limited to, applying a resist film (e.g., spin-coatinga photoresist film) onto the substrate, exposing the resist with animage of a circuit layout (e.g., the geometric pattern of one or moreconductive traces), heat treating the resist, developing the resist,transferring the layout onto the substrate, and removing the remainingresist. Transferring the layout onto a ferromagnetic microstructure 102can include, but is not limited to, using techniques like subtractivetransfer, etching, additive transfer, selective deposition, impuritydoping, ion implantation, and the like. Among conductive materialsexamples include, but are not limited to, metals (e.g., copper, nickel,or the like), metallic inks, metalized plastics, conductive polymers,conductive glasses, conductive composites, or the like.

In an embodiment, one or more of the ferromagnetic microstructures 102include one or more radio frequency transparent materials. Among radiofrequency transparent materials, examples include, but are not limitedto, glass (e.g., glass fibers), KEVLAR®, thermoplastic materials (e.g.,polyester or polyethylene terephthalate (PET), MYLAR®), polyimide (e.g.,Kapton™), fluorinated ethylene propylene (FEP) (e.g.,polytetrafluoroethylene (PTFE) TEFLON®), and the like. See, e.g., U.S.Pat. No. 7,236,142 (issued Jun. 26, 2007) (the contents of which areincorporated herein by reference).

In an embodiment, one or more of the ferromagnetic microstructures 102are configured to limit penetration of electromagnetic fields into atleast a portion of the void 106. In an embodiment, one or more of theferromagnetic microstructures 102 are configured to limit an externalself-generated field. In an embodiment, one or more of the ferromagneticmicrostructures 102 are configured to limit an external self-generatedfield moment. In an embodiment, one or more of the ferromagneticmicrostructures 102 include one or more radio frequency transparentcoating materials. In an embodiment, one or more of the ferromagneticmicrostructures 102 include one or more radio frequency shieldingmaterials. In an embodiment, one or more of the ferromagneticmicrostructures 102 include one or more conductive layers. In anembodiment, one or more of the ferromagnetic microstructures 102 includeone or more RF-shielding cages (e.g., a Faraday cage). In an embodiment,an average major dimension of a hole in the RF-shielding cage is lessthan the wavelength of the shielded electromagnetic radiation.

In an embodiment, one or more of the ferromagnetic microstructures 102include one or more RF-shields. For example, one or more of theferromagnetic microstructures 102 can include one or more thin metalperforated coatings. The dimensions of the perforations are determinedbased on the wavelength of the interference to be limited or blocked bythe RF shield. In an embodiment, an average major dimension of theperforations in the thin metal perforated coatings is less than thewavelength of the shielded electromagnetic radiation. In an embodiment,an average major dimension of the perforations in the thin metalperforated coatings is less than about ½ the wavelength of the shieldedelectromagnetic radiation. In an embodiment, an average major dimensionof the perforations in the thin metal perforated coatings is less thanabout 1/10 the wavelength of the shielded electromagnetic radiation.See, e.g., U.S. Pat. No. 7,371,977 (issued May 13, 2008), the contentsof which are incorporated herein by reference). In an embodiment, anaverage major dimension of the perforations in the thin metal perforatedcoatings range from less than about 1/10 the wavelength of the shieldedelectromagnetic radiation to less than about ½ the wavelength of theshielded electromagnetic radiation. In an embodiment, an average majordimension of the perforations in the thin metal perforated ranges fromabout 1/10 the wavelength of the shielded electromagnetic radiation toabout a wavelength of the shielded electromagnetic radiation. In anembodiment, an average major dimension of the perforations in the thinmetal perforated ranges from about 1/10 the wavelength of the shieldedelectromagnetic radiation to about ½ the wavelength of the shieldedelectromagnetic radiation.

An aspect includes a multiplex nuclear magnetic resonance imagingcomposition including among other things, a plurality of ferromagneticmicrostructure sets. A non-limiting approach includes, among otherthings, multiplex MRI systems, devices, methods, and compositionsincluding microstructure sets of varying internal magnetic fieldmagnitudes. An aspect includes, among other things, multiplex nuclearmagnetic resonance imaging systems, devices, methods, and compositions.A non-limiting approach includes, among other things, multiplex systems,devices, methods, and compositions. A non-limiting approach includessystems, devices, methods, and compositions of multiplex interrogationof a biological sample. A non-limiting approach includes systems,devices, methods, and compositions for obtaining a non-external magneticfield resonance image of a region within a biological subject.

In an embodiment, at least one of the ferromagnetic microstructure setsincludes a different characteristic time-invariant magnetic field 108from another of the ferromagnetic microstructure sets. In an embodiment,each ferromagnetic microstructure set includes one or more ferromagneticmicrostructures configured to include an accessible internal void 106and configured to generate a characteristic time-invariant magneticfield 108 within the accessible internal void 106. In an embodiment,each ferromagnetic microstructure set includes a differentcharacteristic time-invariant magnetic field 108 magnitude. In anembodiment, each ferromagnetic microstructure set includes a differentaccessible internal void 106 dimension. In an embodiment, eachferromagnetic microstructure set includes a different ferromagneticmaterial. In an embodiment, each ferromagnetic microstructure set isconfigured to affect at least one of an in vivo non-zero spin nucleitransverse magnetic relaxation time or an in vivo non-zero spin nucleilongitudinal magnetic relaxation time.

In an embodiment, each ferromagnetic microstructure set comprises adifferent characteristic magnetic field spatial distribution. In anembodiment, a plurality of ferromagnetic microstructure sets include atleast a first ferromagnetic microstructure set including one or moreferromagnetic microstructures configured to generate a first magneticfield spatial distribution within an accessible internal void and asecond ferromagnetic microstructure set including one or moreferromagnetic microstructures configured to generate a second magneticfield spatial distribution within an accessible internal void. In anembodiment, the second magnetic field spatial distribution is differentfrom the spatial distribution of the first magnetic field spatialdistribution.

In an embodiment, one or more of the ferromagnetic microstructures 102include a sufficient amount of at least one ferromagnetic material togenerate a time-invariant magnetic field 108 within the void 106. In anembodiment, one or more of the ferromagnetic microstructures 102 includea sufficient amount of at least one ferromagnetic material to elicit amagnetic resonance response from a biological sample while thebiological sample is received within the void 106. In an embodiment, oneor more of the ferromagnetic microstructures 102 include a sufficientamount of at least one ferromagnetic material to affect at least one ofan in vivo non-zero spin nuclei transverse magnetic relaxation time(e.g., spin ½ nuclei transverse magnetic relaxation time) or an in vivonon-zero spin nuclei longitudinal magnetic relaxation time (e.g., spin ½nuclei longitudinal magnetic relaxation time). In an embodiment, one ormore of the ferromagnetic microstructures 102 include a sufficientamount of at least one ferromagnetic material to change a magneticresonance response of a biological sample present within the void 106.

In an embodiment, at least one of the ferromagnetic microstructures 102is configured to generate a constant magnetic field confined within avolumetric footprint occupied by the ferromagnetic microstructure 102.

In an embodiment, one or more of the ferromagnetic microstructures 102include a sufficient amount of at least one ferromagnetic material toelicit a substantially homogeneous polarizing magnetic field regionwithin the void 106. In an embodiment, a plurality of ferromagneticmicrostructures 102 includes at least a first plurality of ferromagneticmicrostructures sized and dimensioned to generate a first magnetic fluxdensity within the void 106 and a second plurality of ferromagneticmicrostructures sized and dimensioned to generate a second magnetic fluxdensity within the void 106. In an embodiment, the second magnetic fluxdensity is different from the first magnetic flux density. In anembodiment, a plurality of ferromagnetic microstructures 102 includes atleast a first plurality of ferromagnetic microstructures configured togenerate a time-invariant magnetic field within the void 106 of a firstmagnetic field strength and a second plurality of ferromagneticmicrostructures configured to generate a time-invariant magnetic fieldwithin the void 106 of a second magnetic field strength. In anembodiment, the second magnetic field strength is different from thefirst magnetic field strength. In an embodiment, a plurality offerromagnetic microstructures 102 includes at least a first plurality offerromagnetic microstructures sized and dimensioned to generate atime-invariant magnetic field within the void 106 of a first magneticfield strength and a second plurality of ferromagnetic microstructuressized and dimensioned to generate a time-invariant magnetic field withinthe void 106 of a second magnetic field strength. In an embodiment, thesecond magnetic field strength is different from the first magneticfield strength. In an embodiment, at least some of the plurality offerromagnetic microstructures 102 differ in at least one of atime-invariant magnetic field strength, a number of time-invariantmagnetic fields, a void density, an amount of ferromagnetic materials,or a ferromagnetic composition. In an embodiment, a plurality offerromagnetic microstructures 102 comprise one or more differentmagnetic field strengths.

In an embodiment, at least one of the ferromagnetic microstructures 102includes one or voids 106. In an embodiment, the ferromagneticmicrostructures 102 are configured to define one or voids 106 having anygeometric form including regular or irregular forms and having across-section of substantially any shape including, but not limited to,circular, triangular, square, rectangular polygonal, regular orirregular shapes, or the like, as well as other symmetrical andasymmetrical shapes, or combinations thereof. In an embodiment, aplurality of ferromagnetic microstructures 102 includes at least a firstplurality of ferromagnetic microstructures sized and dimensioned togenerate at least a first time-invariant magnetic field within the void106 and a second plurality of ferromagnetic microstructures sized anddimensioned to generate at least a second time-invariant magnetic fieldwithin the void 106. In an embodiment, the characteristic magnetic fieldspatial distribution of the second magnetic field is different from thecharacteristic magnetic field spatial distribution of the first magneticfield.

The ferromagnetic microstructures 102 may take any geometric formincluding regular or irregular forms and may have a cross-section ofsubstantially any shape including, but not limited to, circular,triangular, square, rectangular polygonal, regular or irregular shapes,or the like, as well as other symmetrical and asymmetrical shapes, orcombinations thereof In an embodiment, an average major dimension of atleast some of the plurality of ferromagnetic microstructures 102 rangesfrom less than about thousands of micrometers to less than abouthundreds of nanometers.

In an embodiment, an average major dimension of at least some of theplurality of ferromagnetic microstructures 102 ranges from about tens ofnanometers to about thousands of micrometers. In an embodiment, anaverage major dimension of at least some of the plurality offerromagnetic microstructures 102 ranges from less than about hundredsof micrometers to less than about hundreds of nanometers. In anembodiment, an average major dimension of at least some of the pluralityof ferromagnetic microstructures 102 ranges from less than about onemicrometer to less than about 100 micrometers. In an embodiment, anaverage major dimension of at least some of the plurality offerromagnetic microstructures 102 ranges from less than about 100nanometers to less than about 10⁷ nanometers. In an embodiment, anaverage major dimension of one or more of the plurality of ferromagneticmicrostructures 102 ranges from less than about 1 micrometer to lessthan about 100 micrometers

In an embodiment, an average major dimension of at least some of theplurality of ferromagnetic microstructures 102 is in the order of atleast one of bacteria (e.g., from about 0.2 μm to about 5 μm), basophils(e.g., from about 12 μm to about 15 μm), endothelial cell (e.g., fromabout 10 to about 20 μm), eosinophils (e.g., from about 10 μm to about12 μm), erythrocytes (e.g., from about 6 μm to about 8 μm), lymphocytes(e.g., from about 7 μm to about 8 μm), macrophages (e.g., from about 21μm), mammalian cells, monocytes (e.g., from about 14 μm to about 17 μm),neutrophils (e.g., from about 10 to about 12 μm), or viruses (e.g., fromabout 5×10⁻³ μm to 0.1 μm) (e.g., from a picornavirus (ranging in sizefrom about 22 nm to about 30 nm) to poxviruses (ranging in size formabout 240 nm to about 300 nm). In an embodiment, an average majordimension of at least some of the plurality of ferromagneticmicrostructures 102 is at least less than an order of magnitude of about10 micrometers. In an embodiment, an average particles size distributionof the plurality of ferromagnetic microstructures ranges from about 10nanometers to about 1 millimeter.

In an embodiment, an average major dimension of at least some of theplurality of ferromagnetic microstructures 102 is less than an order ofmagnitude of a capillary diameter (e.g., from about 5 to about 10 μm).In an embodiment, an average major dimension of at least some of theplurality of ferromagnetic microstructures 102 is less than an order ofmagnitude of a space between lateral endothelial cells in blood vessel(e.g., from about 10 to about 20 nm). In an embodiment, an average majordimension of at least some of the plurality of ferromagneticmicrostructures 102 is in the order of a quantum dot (e.g., from about10 to 50 nm). In an embodiment, an average major dimension of at leastsome of the plurality of ferromagnetic microstructures 102 is in theorder of a plasma membrane thickness (e.g., from about 3 to about 10nm).

An aspect includes systems, devices, and methods employing compositionsincluding, among other things, targeted ferromagnetic microstructures. Anon-limiting approach includes systems, devices, methods, andcompositions including, among other things, targeted ferromagneticmicrostructures. A non-limiting approach includes systems, devices,methods, and compositions for detecting a magnetic resonance eventassociated with one or more nuclear magnetic resonance detectable nucleiexposed to a static magnetic field within one or more surface-definedvoids 106 of a plurality of target-selective microstructures.

In an embodiment, one or more ferromagnetic microstructures 102 of aplurality of ferromagnetic microstructures are configured to selectivelyinterrogate a region of the biological subject. In an embodiment, one ormore ferromagnetic microstructures 102 of a plurality of ferromagneticmicrostructures are configured to selectively interrogate a tissue ofthe biological subject. In an embodiment, one or more ferromagneticmicrostructures 102 of the a plurality of ferromagnetic microstructures102 are configured to selectively-target one or more regions of thebiological subject.

In an embodiment, at least one of the ferromagnetic microstructures 102includes one or more targeting moieties 112. For example, one or more ofthe ferromagnetic microstructures 102 may incorporate one or moretargeting moieties 112 that selectively target one or more of theferromagnetic microstructures 102 to specific tissues, cells, genomictargets, biological targets, or the like. In an embodiment, one or moreof the ferromagnetic microstructures 102 may incorporate one or moretargeting moieties 112 to target the ferromagnetic microstructures 102to a target in, on, or outside a cell. In an embodiment, a multiplexmethod includes a plurality of target-selective microstructures foridentifying one or more factors associated with a specific diseasestate, pathology, or condition by targeting with one or more targetingmoieties 112.

Among the one or more targeting moieties 112, examples include, but arenot limited to, a cell surface receptor targeting moiety, atransmembrane molecule targeting moiety, an antigen targeting moiety, animmune-receptor targeting moiety, a folate receptor targeting moiety,and the like. Further examples of targeting moieties 112 include, butare not limited to, antibodies or fragments thereof, oligonucleotide orpeptide based aptamers, receptors or parts thereof, receptor ligands orparts thereof, lectins, artificial binding substrates formed bymolecular imprinting, biomolecules, humanized targeting moieties, mutantor genetically engineered proteins, mutant or genetically engineeredprotein binding domains, adhesion proteins, e.g., integrins, mucins,fibronectins, and substrates (e.g., poly-lysine, collagen, Matrigel,fibrin) that interact with components of tissues or cells, and the like.

Further examples of targeting moieties 112 include, but are not limitedto, an antibody that binds one or more targets on a tissue or cellsurface such as, for example, a cell surface receptor, a transmembranereceptor, an immune receptor, as well as biomolecules on, or in closeproximity to, a target tissue or cell. Among antibodies or fragmentsthereof for use as targeting moieties 112, examples include, but are notlimited to, monoclonal antibodies, polyclonal antibodies, chimericantibodies, rabbit antibodies, chicken antibodies, mouse antibodies,human antibodies, humanized antibodies or antibody fragments, Fabfragments of antibodies, F(ab′)₂ fragments of antibodies, single-chainvariable fragments (scFvs) of antibodies, diabody fragments (dimers ofscFv fragments), minibody fragments (dimers of scFvs-C_(H)3 with linkeramino acid), and the like. Further examples of antibodies or fragmentsinclude, but are not limited to, bispecific antibodies, trispecificantibodies, single domain antibodies (e.g., camel and llama VHH domain),lamprey variable lymphocyte receptor proteins, antibodies based onproteins or protein motifs (for example lipocalins, fibronectins,ankyrins and src-homology domains.

Among antibodies, examples include, but are not limited to,immunoglobulin molecules including four polypeptide chains, two heavy(H) chains and two light (L) chains inter-connected by disulfide bonds.Each heavy chain includes a heavy chain variable region (VH) and a heavychain constant region. The heavy chain constant region includes threedomains, CH1, CH2 and CH3. Each light chain includes a light chainvariable region (VL) and a light chain constant region. The light chainconstant region includes one domain, CL. The VH and VL regions can befurther subdivided into regions of hypervariability, termedcomplementarity determining regions (CDRs), interspersed with regionsthat are more conserved, termed framework regions (FR). Each VH and VLincludes three complementarity determining regions and four frameworkregions, arranged from amino-terminus to carboxy-terminus in thefollowing order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. (See, e.g., U.S.Pat. No. 7,504,485 (issued Mar. 17, 2009), the contents of which areincorporated herein by reference). The pairing of VH and VL togetherforms a single antigen-binding portion of the antibody.

Among antibody fragments, examples include, but are not limited to,fragments of an antibody that retain the ability to specifically bind toan antigen (e.g., antigen-binding portions). It has been shown that theantigen-binding function of an antibody can be performed by fragments ofa full-length antibody. Examples of binding fragments include, but arenot limited to single domain antibodies (dAb) fragments (e.g., thoseincluding a single VH domain), F(ab′)₂ fragments (e.g., a bivalentfragment including two Fab fragments linked by a disulfide bridge at thehinge region), Fab fragments (e.g., a monovalent fragment including VL,VH, CL and CH1 domains), Fd fragments (e.g., those including VH and CH1domains), Fv fragments (e.g., those including VL and VH domains of asingle arm of an antibody), single chain Fv (linear fragment containingVH and VL regions separated by a short linker), diabodies (two singlechain Fv fragments separated by short linkers), and the like. See e.g.,the following documents (the contents of which are incorporated hereinby reference): Bird et al., Science 242:423-426 (1988); Ward et al.,Nature 341:544-546 (1989); and Huston et al., Proc. Natl. Acad. Sci. USA85:5879-5883(1988).

Examples of diabodies include, but are not limited to, bivalent,bispecific antibodies having VH and VL domains expressed on a singlepolypeptide chain, but using a linker that is too short to allow forpairing between the two domains on the same chain (thereby forcing thedomains to pair with complementary domains of another chain and creatingtwo antigen binding sites). See e.g., the following documents (thecontents of which are incorporated herein by reference): Holliger, P.,et al., Proc. Natl. Acad. Sci. USA 90:6444-6448 (1993); Poljak, R. J.,et al., Structure 2:1121-1123 (1994).

Alternatively, an antibody or antigen-binding portion thereof may bepart of a larger immunoadhesion molecule, formed by covalent ornon-covalent association of the antibody or antibody portion with one ormore other proteins or peptides. See e.g., the following documents (thecontents of which are incorporated herein by reference): Kipriyanov, S.M., et al., Human Antibodies and Hybridomas 6:93-101 (1995) andKipriyanov, S. M., et al., Mol. Immunol. 31:1047-1058 (1994).

Antibody portions, such as Fab and F(ab′)₂ fragments, are prepared fromwhole antibodies using conventional techniques, such as papain or pepsindigestion, respectively, of whole antibodies. Antibodies, antibodyportions and immunoadhesion molecules, and the like can be obtainedusing standard recombinant DNA techniques.

In an embodiment, one or more of the targeting moieties 112 includesingle chain or multiple chain antigen-recognition motifs, epitopes, ormimotopes. In an embodiment, the multiple chain antigen-recognitionmotifs, epitopes, or mimotopes can be fused or unfused. Among antibodiesor fragments thereof, examples include, but are not limited to,antibodies or fragments thereof generated using, for example, standardmethods such as those described by Harlow & Lane (Antibodies: ALaboratory Manual, Cold Spring Harbor Laboratory Press; 1^(st) edition1988) (the contents of which are incorporated herein by reference). Inan embodiment, an antibody or fragment thereof may be generated usingphage display technology. See, e.g., Kupper, et al. BMC Biotechnology5:4 (2005) (the contents of which are incorporated herein by reference).An antibody or fragment thereof could also be prepared using, forexample, in silico design. See, e.g., Knappik et al., J. Mol. Biol. 296:57-86 (2000) (the contents of which are incorporated herein byreference).

In an embodiment, at least one targeting moiety 112 associated with aferromagnetic microstructure 102 is a diagnostic or therapeutic antibodyor antibody fragment approved for use in humans by the U.S. Food andDrug Administration (FDA). Examples of FDA approved antibodies include,but are not limited to, abciximab, adalimumab, alemtuzumab, arcitumomab,basiliximab, bevacizumab, capromab pendetide, cetuximab, daclizumab,efalizumab, gemtuzumab, ibritumomab tiuxetan, infliximab, muromonab-CD3,nimotuzumab, nofetumomab, omalizumab, palivizumab, rituximab,tocilizumab, tositumomab, trastuzumab, and the like. Examples of otherdiagnostic or therapeutic antibodies include adecatumumab, apolizumab,bavituximab, belimumab, cixutumumab, conatumumab, denosumab,edrecolomab, epratuzumab, etaracizumab, farletuzumab, figitumumab,gantenerumab, golimumab, iratumumab, lerdelimumab, lexatumumab,lintuzumab, lucatumumab, mapatumumab, metelimumab, necitumumab,ofatumumab, panitumumab, pritumumab, robatumumab, stamulumab, votumumab,zalutumumab, zanolimumab, and the like.

In an embodiment, one or more ferromagnetic microstructures 102 includeat least one targeting moiety 112 directed to gene expression products.For example, in an embodiment, a targeting moiety 112 may specificallytarget a gene, an mRNA, a microRNA, a gene product, a protein, aglycosylation of a gene product, a substrate or metabolite of a geneproduct, or the like. See, e.g., U.S. Patent Publ. No. 2008-0206152(published Aug. 28, 2008) (the contents of which are incorporated hereinby reference). In an embodiment, one or more targeting moieties 112 areconfigured to target a compound directly associated with gene expression(e.g., transcription factors, acetylated histones, zinc finger proteins,translation factors, a metabolite of an enzyme, or the like).

In an embodiment, one or more of the targeting moieties 112 areconfigured to target an in vivo component in, on, or outside a cell.Among in vivo targets, examples include, but are not limited to,carbohydrates, cell surface proteins (e.g., cell adhesion molecules,cell surface polypeptides, membrane receptors, or the like), cytosolicproteins, intracellular components (e.g., one or more components of asignaling cascade such as, for example, one or more signaling molecules,kinases, phosphatases, transcription factors, signaling peptides,signaling proteins, or the like), metabolites, nuclear proteins,receptors, and secreted proteins (e.g., growth factors, cell signalingmolecules, or the like).

In an embodiment, one or more of the targeting moieties 112 include atleast one NANOBODY (e.g., single domain antibodies, single-chainantibody fragments (VHH), NANOBODIES (Ablynx nv Belgium), or the like,or fragments thereof). VHHs have been developed against various tissueand cell targets, examples of which include lipopolysaccharide (sepsis),carcinoembryonic antigen (CEA; cancer), and the epidermal growth factorreceptor (cancer) (see, e.g., Harmsen, et al., Appl. Microbiol.Biotechnol. 77:31-22 (2007), the contents of which are incorporatedherein by reference). In an embodiment, one or more of the targetingmoieties 112 include at least one heavy chain, single N-terminal domainantibody that does not require domain pairing for antigen recognition.

In an embodiment, one or more of the targeting moieties 112 include atleast one oligonucleotide RNA or DNA based aptamer. Aptamers areoligonucleotides (DNA or RNA) that can bind to a wide variety ofentities (e.g., metal ions, small organic molecules, proteins, or cells)with high selectivity, specificity, and affinity. Aptamers may beisolated from a large library of about 10¹⁴ to about 10¹⁵ randomoligonucleotide sequences using an iterative in vitro selectionprocedure often termed “systematic evolution of ligands by exponentialenrichment” (SELEX). See, e.g., Cao, et al., Current Proteomics 2:31-40,2005; Proske, et al., Appl. Microbiol. Biotechnol. 69:367-374 (2005);Jayasena Clin. Chem. 45:1628-1650 (1999); (the contents of which areincorporated herein by reference). Or an aptamer may be syntheticallycreated and screened or its sequence devised in silico. In anembodiment, an aptamer library is screened against one or more targetsof interest. For example, an RNA aptamer may be generated againstleukemia cells using a cell based SELEX method. See, e.g., Shangguan, etal., Proc. Natl. Acad. Sci. USA 103:11838-11843 (2006) (the contents ofwhich are incorporated herein by reference). Similarly, an aptamer thatrecognizes bacteria may be generated using the SELEX method againstwhole bacteria. See, e.g., Chen, et al., Biochem. Biophys. Res. Commun.357:743-748 (2007) (the contents of which are incorporated herein byreference). In an embodiment, one or more of the targeting moieties 112include at least one peptide based aptamer. Among peptide basedaptamers, examples include, but are not limited to, an artificialprotein where inserted peptides are expressed as part of a primarysequence of a structurally stable protein or scaffold. See, e.g.,Crawford et al., Peptide Aptamers: Tools for Biology and Drug Discovery,Briefings in Functional Genomics and Proteomics, 2 (1): 72-79 (2003)(the contents of which are incorporated herein by reference).

In an embodiment, one or more of the targeting moieties 112 include allor part of a naturally occurring ligand that binds to, for example, areceptor on a surface of tissue or cells of interest. In an embodiment,one or more of the targeting moieties 112 include all or part of apeptide hormone, examples of which include, but are not limited to,neuropeptides, (e.g., enkephalins, neuropeptide Y, somatostatin,corticotropin-releasing hormone, gonadotropin-releasing hormone,adrenocorticotropic hormone, melanocyte-stimulating hormones,bradykinins, tachykinins, cholecystokinin, vasoactive intestinal peptide(VIP), substance P, neurotensin, vasopressin, calcitonin, or the like);cytokines (e.g., interleukins (e.g., IL-1 through IL-35),erythropoietin, thrombopoietin, interferon (IFN), granulocyte monocytecolony-stimulating factor (GM-CSF), tumor necrosis factor (TNF), or thelike); chemokines (e.g., RANTES, TARC, MIP-1, MCP, or the like); growthfactors (e.g., platelet derived growth factor (PDGF), transforminggrowth factor beta (TGFβ), nerve growth factor (NGF), epidermal growthfactor (EGF), insulin-like growth factor (IGF), basic fibroblast growthfactor (bFGF), vascular endothelial growth factor (VEGF), or the like);other peptide hormones (e.g., atrial natriuretic factor, insulin,glucagon, angiotensin, prolactin, oxyocin, or the like), and the like.

Other examples of peptides that could be used as targeting moieties 112include, but are not limited to, those found in venomous snakes,insects, or plants. For example, chlorotoxin (CTX), a 36 amino acidpeptide isolated from the deathstalker scorpion (Leiurusquinquestriatus), binds preferentially to glioma cells relative tonormal glial cells and other cells of the central nervous system(Soroceanu, et al., Cancer Res. 58:4871-4879 (1998), the contents ofwhich are incorporated herein by reference). Examples of other peptidetoxins include, but are not limited to, botulinum toxin, agatoxin,charybdotoxin, conotoxin, dendrotoxin, iberiotoxin, kaliotoxin, andtityustoxin. These peptide toxins preferentially interact with membraneassociated calcium, sodium, chloride or potassium channels and as such,may be used as targeting moieties 112 to target, for example, ionchannels.

In an embodiment, one or more of the targeting moieties 112 include an“universal cell-recognition site” binding tripeptidearginine-glycine-aspartic acid (RGD) or analogs thereof. RGD and RGDanalogs preferentially interact with members of the transmembranespanning integrin gene family and may be used to target integrinsassociated with diseased states. For example, the RGD peptide may beused as a targeting moiety to target tumor cells expressing increasedlevels of the integrin alpha_(v)-beta₃ (Liu, et. al., ACS Nano 1:50-56(2007), the contents of which are incorporated herein by reference).

In an embodiment, one or more of the targeting moieties 112 include oneor more novel ligands identified using a peptide phage library. See,e.g., Bonetto, et al., FASEB J. 23:575-585 (2009) (the contents of whichare incorporated herein by reference). In an embodiment, phage areengineered to express a library of novel peptides on their surface asfusion proteins in association with a phage major or minor coat protein.The peptide phage library can be screened against cultured transformedcells lines such as, for example, U87-MG human malignant glioma cells oragainst primary tumors from patients with various cancers such as, forexample, breast and pancreatic cancer and melanoma (see, e.g., Spear, etal. Cancer Gene Therapy 8:506-511 (2001); Krag, et al. Cancer Res.66:7724-7733 (2006). In an embodiment, a cancer targeting ligand may beidentified by screening a random peptide library against a cancer targetusing a yeast two-hybrid screen. See, e.g., Nauenburg, et al. FASEB J.15:592-594 (2001).

In an embodiment, one or more of the targeting moieties 112 include oneor more small chemical compound ligands that interact with a cognate ona target cell, such as a receptor. Examples of small chemical compoundligands include, but are not limited to, acetylcholine, adenosinetriphosphate (ATP), adenosine, androgens, dopamine, endocannabinoids,epinephrine, folic acid, gamma-aminobutyric acid (GABA),glucocorticoids, glutamate, histamine, leukotrienes, mineralocorticoids,norepinephrine, prostaglandins, serotonin, thromoxanes, and vitamins. Inan embodiment, one or more of the ferromagnetic microstructures 102 aremodified with folic acid, such that the modified microstructures maybetargeted to folate receptors overexpressed on some tumor cells. See,e.g., Kranz et al., Proc. Natl. Acad. Sci. USA 92:9057-9061 (1995) (thecontents of which are incorporated herein by reference)

In an embodiment, one or more of the targeting moieties 112 include oneor more synthetic small molecule compounds such as an agonist orantagonist that interact with a target on, or in proximity to, a cell ortissue. Among agonists, antagonists, or other small molecule compounds,examples include, but are not limited to, those approved by the U.S.Food and Drug Administration (FDA) for use in humans such as, forexample, those listed in Remington: The Science and Practice ofPharmacy, 21^(st) Edition, 2005, edited by David Troy, LippincottWilliams & Wilkins, Baltimore Md. In an embodiment, at least one of theferromagnetic microstructures 102 is conjugated to a leukotriene B4receptor antagonist for use, for example, as MRI contrast agents fordetection of infection and inflammation. See, e.g., U.S. Patent Pub No.2008/0213181 (published Sep. 4, 2008) (the contents of which areincorporated herein by reference).

In an embodiment, one or more of the targeting moieties 112 include oneor more lectins. Among lectins, examples include, but are not limitedto, agglutinins that could discriminate among types of red blood cellsand cause agglutination, sugar-binding proteins from many sourcesregardless of their ability to agglutinate cells, and the like. Lectinshave been found in plants, viruses, microorganisms and animals. Becauseof the specificity that each lectin has toward a particular carbohydratestructure, even oligosaccharides with identical sugar compositions maybe distinguished or separated. Some lectins will bind only to structureswith mannose or glucose residues, while others may recognize onlygalactose residues. Some lectins require that a particular sugar be in aterminal non-reducing position in the oligosaccharide, while others canbind to sugars within the oligosaccharide chain. Some lectins do notdiscriminate between a and b anomers, while others require not only thecorrect anomeric structure but also a specific sequence of sugars forbinding.

Further examples of lectins include, but are not limited to, algallectins (e.g., b-prism lectin); animal lectins (e.g., tachylectin-2,C-type lectins, C-type lectin-like, calnexin-calreticulin, capsidprotein, chitin-binding protein, ficolins, fucolectin, H-type lectins,I-type lectins, sialoadhesin, siglec-5, siglec-7, micronemal protein,P-type lectins, pentrxin, b-trefoil, galectins, congerins, selenocosmiahuwena lectin-I, Hcgp-39, Ym1); bacterial lectins (e.g., PseudomonasPA-IL, Burkholderia lectins, chromobacterium CV-IIL, Pseudomonas PA IIL,Ralsonia RS-ILL, ADP-ribosylating toxin, Ralstonia lectin, Clostridiumhemagglutinin, botulinum toxin, tetanus toxin, cyanobacterial lectins,FimH, GafD, PapG, Staphylococcal enterotoxin B, toxin SSL11, toxinSSL5); fungal and yeast lectins (e.g., Aleuria aurantia lectin,integrin-like lectin, Agaricus lectin, Sclerotium lectin, Xerocomuslectin, Laetiporus lectin, Marasmius oreades agglutinin, agrocybegalectin, coprinus galectin-2, Ig-like lectins, L-type lectins); plantlectins (e.g., alpha-D-mannose-specific plant lectins, amaranthusantimicrobial peptide, hevein, pokeweed lectin, Urtica dioica UD, wheatgerm WGA-1, WGA-2, WGA-3, artocarpin, artocarpus hirsute AHL, bananalectin, Calsepa, heltuba, jacalin, Maclura pomifera MPA, MornigaM,Parkia lectins, abrin-a, abrus agglutinin, amaranthin, castor bean ricinB, ebulin, mistletoe lectin, TKL-1, cyanovirin-N homolog, and variouslegume lectins); and viral lectins (e.g., capsid protein, coat protein,fiber knob, hemagglutinin, and tailspike protein) (see, e.g., E.Bettler, R. Loris, A. Imberty 3D-Lectin database: A web site for imagesand structural information on lectins, 3rd Electronic GlycoscienceConference, The internet and World Wide Web, 6-17 October 1997;http://www.cermay.cnrs.fr/lectines/).

In an embodiment, one or more of the targeting moieties 112 include oneor more synthetic elements such as an artificial antibody or othermimetic. Examples of synthetic elements may be found in, for example,the following documents (the contents of which are incorporated hereinby reference): U.S. Pat. No. 5,804,563 (issued Sep. 8, 1998); U.S. Pat.No. 5,831,012 (issued Nov. 3, 1998); U.S. Pat. No. 6,255,461(issued Jul.3, 2001); U.S. Pat. No. 6,670,427 (issued Dec. 30, 2003); U.S. Pat. No.6,797,522 (issued Sep. 28, 2004); U.S. Patent Pub. No. 2004/0018508(published Jan. 29, 2004); Ye and Haupt, Anal Bioanal Chem. 378:1887-1897 (2004); and Peppas and Huang, Pharm Res. 19: 578-587 (2002).

In an embodiment, antibodies, recognition elements, or syntheticmolecules that recognize a cognate may be available from a commercialsource. See, e.g., Affibody® affinity ligands (Abcam, Inc. Cambridge,Mass. 02139-1517; U.S. Pat. No. 5,831,012 (issued Nov. 3, 1998), thecontents of which are incorporated herein by reference).

In an embodiment, one or more of the targeting moieties 112 include oneor more artificial binding substrates formed by, for example, molecularimprinting techniques and methodologies. A more detailed discussion ofmolecular imprinting can be found in, for example, the followingdocuments (the contents of which are incorporated herein by reference):U.S. Pat. No. 7,442,754 (issued Oct. 28, 2008), U.S. Pat. No. 7,288,415(issued Oct. 30, 2007), U.S. Pat. No. 6,660,176 (issued Dec. 9, 2003),and U.S. Pat. No. 5,801,221 (issued Sep. 1, 1998). In an embodiment, atarget template is combined with functional monomers which, uponcross-linking, forms a polymer matrix that surrounds the targettemplate. Removal of the target template leaves a stable cavity in thepolymer matrix that is complementary in size and shape to the targettemplate. As such, functional monomers of a polymer forming matrix suchas acrylamide and ethylene glycol dimethacrylate, for example, can bemixed with one or more cytokine in the presence of a photoinitiator suchas 2,2-azobis(isobutyronitrile). The monomers can be cross-linked to oneanother using ultraviolet irradiation. The resulting polymer may becrushed or ground into smaller pieces and washed to remove the one ormore cytokine, leaving a particulate matrix material capable of bindingone or more cytokine. Examples of other functional monomers,cross-linkers and initiators useful to generate an artificial bindingsubstrate have been described elsewhere (see, e.g., U.S. Pat. No.7,319,038 (issued Jan. 15, 2008) (the contents of which are incorporatedherein by reference).

In an embodiment, one or more of the targeting moieties 112 areconfigured to target RNA or DNA. Examples of targeting moieties 112 thatbind RNA or DNA include, but are not limited to, microRNA, anti-senseRNA, small interfering RNA (siRNA), anti-sense oligonucleotides,protein-nucleic acids (PNAs). For example, Bartlett et al., describemodifying ⁶⁴Cu-labeled nanoparticles with a specific siRNA for use intumor localization by positron emission tomography (Bartlett et al.,Proc. Natl. Acad. Sci., USA. 104:15549-15554 (2007), the contents ofwhich are incorporated herein by reference). Similarly, Yezhelyev, etal., describe siRNA linked to proton-sponge-coated quantum dots forintracellular imaging (Yezhelyev, et al., J. Am. Chem. Soc.130:9006-9012 (2008), the contents of which are incorporated herein byreference).

Referring to FIGS. 1C, 1D, and 1E, in an embodiment, at least a firstinternal surface 104 of at least one of the plurality of ferromagneticmicrostructures 102 includes one or more targeting moieties 112. In anembodiment, at least an outer surface 110 of at least one of theplurality of ferromagnetic microstructures 102 includes one or moretargeting moieties 112. In an embodiment, a majority of the one or moretargeting moieties 112 is localize to a portion of the void 106including a time-invariant magnetic field 108.

In an embodiment, at least one of the plurality of ferromagneticmicrostructures 102 includes one or more targeting moieties 112 aattached to at least a first internal surface 104. In an embodiment, atleast one of the plurality of ferromagnetic microstructures 102 includesone or more targeting moieties 112 b attached to an outer surface 110.In an embodiment, at least one of the plurality of ferromagneticmicrostructures 102 includes one or more targeting moieties 112 aattached to at least a first internal surface 104 and one or moretargeting moieties 112 b attached to an outer surface 110. In anembodiment, the one or more targeting moieties 112 a attached to thefirst internal surface 104 differ from the one or more targetingmoieties 112 b attached to the outer surface 110.

In an embodiment, a plurality of ferromagnetic microstructures 102include two or more different targeting moieties 112. In an embodiment,a plurality of ferromagnetic microstructures 102 include one or moretargeting moieties on an outer surface 110 and one or more targetingmoieties 112 on an inner surface 104. In an embodiment, the one or moretargeting moieties 112 on the outer surface 110 differ from the one ormore targeting moieties 112 on the inner surface 104. In an embodiment,the one or more targeting moieties 112 on the outer surface 110 differin at least one of a target 122 a, a cell-receptor target 122 b, atarget selectivity, or a target specificity from the one or moretargeting moieties 112 on the inner surface 104.

In an embodiment, one or more of the targeting moieties 112 may interactwith or bind to one or more targets on or proximal to a tissue, cellsurface, or the like such as, for example, a cell surface receptor, atransmembrane receptor, immune receptor, or components thereof. In anembodiment, one or more of the targeting moieties 112 may interact withcomponents of vascular circulation system including cells, biomolecules,and infecting pathogens. In an embodiment, the target tissue or targetcell includes a tumor cell or other diseased cell type in a mammaliansubject. Further examples of target cells include, but are not limitedto, one or more pathogens (e.g., virus, bacteria, fungi, or parasite).In an embodiment, the ferromagnetic microstructures 102 are configuredto enter a cell and target a specific cellular organelle (e.g., themitochondria). Among targets associated with a target cell or organelle,examples include, but not limited to, at least one of a protein, acarbohydrate, a glycoprotein, a glycolipid, a sphingolipid, aglycerolipid, or metabolites thereof.

In an embodiment, least one of the ferromagnetic microstructures 102 caninclude one or more targeting moieties 112 that bind to or interact withone or more targets associated with or released by a specific tissue orcell type. Among the one or more targets, examples include, but are notlimited to, those associated with endothelial cells (e.g., VE cadherin,VonWillibrand Factor, thrombomodulin, angiotension-converting enzyme, orthe like), epithelial cells (e.g., cytokeratins, mucins, specific sodiumchannels, surfactant proteins, or the like), neurons, glial cells orastrocytes (e.g., artemin, BDNF, glial filament protein, nerve growthfactor receptor, neuron specific enolase, neurofascin, peripherin,myelin basic protein, NMDA receptor, neurofilament, neuropilins, or thelike), or smooth muscle cells (e.g., smooth muscle actin, cyclicnucleotide phosphodiesterase type 5, or the like). One or more of thetargeting moieties 112 may bind to any of a number of markers specificfor circulating inflammatory cells, for example, T-lymphocytes (e.g.,CD3, CD4, CD8), B-lymphocytes (e.g., CD20), monocytes (e.g., LFA-1alpha, CD163), or granulocytes (e.g., CD66, CD67). In an embodiment, oneor more of the targeting moieties 112 may target a specific organ. Forexample, galactosylated chitosan may be used to specifically target theliver (Kim, et al., J. Nucl. Med. 46:141-145, (2005), the contents ofwhich are incorporated herein by reference). In an embodiment, thetargeting moiety 112 may target a specific pathology. For example,targeting moieties directed to the mannose-6-phosphate receptor may beused to visualize fibrosis (see, e.g., U.S. Patent Pub. No. 2008/0279765(published Nov. 13, 2008), the contents of which are incorporated hereinby reference).

In an embodiment, one or more of the ferromagnetic microstructures 102include one or more targeting moieties 112 that bind one or more targetsassociated with or released by a tumor cell. Examples of targetsassociated with tumor cells include, but are not limited to, androgenreceptor (androgen responsive prostate cancer), BLyS receptor,carcinoembryonic antigen (CEA), CA-125, CA19-9, CD25, CD34, CD33 andCD123 (acute myeloid leukemia), CD20 (chronic lymphocytic leukemia),CD19 and CD22 (acute lymphoblastic leukemia), CD44v6 (epithelial-derivedtumors), CD30, CD40, CD70, CD133, 57 kD cytokeratin, epithelial specificantigen, extracellular matrix glycoprotein tenascin, Fas/CD95,gastrin-releasing peptide-like receptors, hepatocyte specific antigen,HER2 receptor, human gastric mucin, human milk fat globule, lymphaticendothelial cell marker, matrix metalloproteinase 9, melan A, melanomamarker, melanocortin-1 receptor, mesothelin, mucin glycoproteins (e.g.,MUC1, MUC2, MUC4, MUC5AC, MUC6), prostate specific antigen (PSA),prostate specific membrane antigen (PSMA), prostatic acid phosphatase,PTEN, renal cell carcinoma marker, RGD-peptide binding integrins (e.g.,alpha5beta3, alpha5beta6), survivin, sialyl Lewis A, six-transmembraneepithelial antigen of the prostate (STEAP), TAG-72 (colon cancer), TNFreceptor, TRAIL receptor, tyrosinase, villin. Other tumor associatedantigens include, but are not limited to, alpha fetoprotein,apolipoprotein D, clusterin, chromogranin A, myeloperoxidase, MyoD1myoglobin placental alkaline phosphatase c-fos, homeobox genes, and thelike. In an embodiment, the target may be a cell surface receptor orcell surface marker on a tumor cell. In an embodiment, the target may bea biomolecule secreted by a tumor cell.

In an embodiment, one or more of the ferromagnetic microstructures 102include one or more targeting moieties 112 that interact with a targetthat is associated with an immune or inflammatory response. In anembodiment, one or more of the targeting moieties 112 include one ormore immune receptors. Examples of immune receptors include, but are notlimited to, cytokine receptors (e.g., erythropoietin receptor, GM-CSFreceptor, G-CSF receptor, growth hormone receptor, oncostatin Mreceptor, leukemia inhibitory factor receptor, interleukin receptors,interferon-alpha/beta receptors, interferon-gamma receptor, CSF1, c-kitreceptor, interleukin-18 receptor, tumor necrosis factor (TNF) receptorfamily, lymphotoxin beta receptor, chemokine receptors such asinterleukin-8 receptor, CCR1, CXCR4, and TGF beta receptors), Fcreceptors (e.g., Fc-epsilon RI, Fc-epsilon RII, Fc-gamma RI, Fc-gammaRII, Fc-gamma RIII, Fc-alpha RI, and Fc-alpha/mu R), lymphocyte homingreceptors (e.g., CD44, L-selectin, VLA-4, and LFA-1), patternrecognition/toll-like receptors (e.g., TLR1 through TLR10), T-cellreceptors, B-cell receptors, major histocompatibility complex (MHC),complement, immunophilins, integrin, killer-cell immunoglobulin-likereceptors, and the like. A more extensive description of inflammatorymediator receptors can be found in, for example, Ozaki and Leonard, J.Biol. Chem. 277:29355-29358 (2002) (the contents of which areincorporated herein by reference).

In an embodiment, one or more of the ferromagnetic microstructures 102include one or more targeting moieties 112 that interact with specificbiomolecules in the plasma of the vascular circulation such as, forexample, soluble inflammatory mediators. Examples of solubleinflammatory mediators include, but are not limited to, cytokines suchas interferons, interleukins, tumor necrosis factor (TNF), granulocytecolony stimulating factor (G-CSF), granulocyte-macrophage colonystimulating factor (GM-CSF), macrophage colony-stimulating factor(M-CSF), erythropoietin (EPO) and thrombopoietin (TPO), and chemokines.Other examples of inflammatory mediators include, but are not limitedto, leukotrienes, prostaglandins, growth factors, soluble receptors,C-reactive protein, CD11b, histamine, serotonin, apolipoprotein Al,bradykinin, endothelin-1, eotaxin, insulin, IP-10, leptin, lymphotactin,OSM, SGOT TIMP-1, tissue factor, VCAM-1, VWF, thromboxane, plateletactivating factor (PAF), pathogen-derived endotoxins and exotoxins, andthe like.

In an embodiment, one or more of the ferromagnetic microstructures 102include one or more targeting moieties 112 that interact with otherspecific biomolecules in the plasma of the vascular circulation systemincluding. Among, biomolecules in the plasma of the vascular circulationsystem, examples include, but not limited to, albumin and pre-albumin,immunoglobulins, lipoproteins, complement components, alpha-globulins,beta-globulins, retinol binding protein, and coagulation proteins.

In an embodiment, one or more of the ferromagnetic microstructures 102include one or more targeting moieties 112 that bind one or more targetsthat are transmembrane receptors. Examples of transmembrane receptorsinclude, but are not limited to, G protein-coupled receptors (e.g.,muscarinic acetylcholine receptor, adenosine receptor, adrenergicreceptors, GABA receptors, angiotensin receptors, cannabinoid receptors,cholecystokinin receptors, dopamine receptors, glucagon receptors,glutamate receptors, histamine receptors, olfactory receptors, opioidreceptors, rhodopsin, secretin receptors, serotonin receptors,somatostatin receptors, calcium-sensing receptors, chemokine receptors,or the like); receptor tyrosine kinases (e.g., erythropoietin receptor,insulin receptors, epidermal growth factor (EGF) receptors,platelet-derived growth factor (PDGF) receptors, fibroblast growthfactor (FGF) receptors, vascular endothelial growth factor (VEGF)receptors, and Trk receptors, or the like); guanylyl cyclase receptors;ion channels; folate receptors; and the like.

In an embodiment, one or more of a plurality of ferromagneticmicrostructures 102 include one or more targeting moieties 112 attachedto at least one of the plurality of ferromagnetic microstructures 102.In an embodiment, one or more of the targeting moieties 112 include atleast one cell surface receptor-targeting moiety. In an embodiment, oneor more of the targeting moieties 112 include at least one transmembranereceptor-targeting moiety. In an embodiment, one or more of thetargeting moieties 112 include at least one antigen-targeting moiety. Inan embodiment, one or more of the targeting moieties 112 include atleast one immune-receptor targeting moiety. In an embodiment, one ormore of the targeting moieties 112 include at least one folate receptortargeting moiety. In an embodiment, one or more of the targetingmoieties 112 include at least one nucleotide binding moiety. In anembodiment, one or more of the targeting moieties 112 include at leastone oligodeoxyribonucleotide binding moiety. In an embodiment, one ormore of the targeting moieties 112 include at least oneoligoribonucleotide binding moiety. In an embodiment, one or more of thetargeting moieties 112 include at least one peptide nucleic acid. In anembodiment, one or more of the targeting moieties 112 include at leastone aptamer. In an embodiment, one or more of the targeting moieties 112include at least one antibody or antibody fragment.

In an embodiment, one or more of the targeting moieties 112 include atleast one amyloid binding moiety. In an embodiment, one or more of thetargeting moieties 112 include at least one β-amyloid binding moiety. Inan embodiment, one or more of the targeting moieties 112 include atleast one thioflavin derivative. In an embodiment, the one or moretargeting moieties 112 include at least one2-[4′-(methylamino)phenyl]benzothiazole derivative. In an embodiment,one or more of the targeting moieties 112 include at least one 2-arylbenzothiazole derivative. In an embodiment, one or more of the targetingmoieties 112 include at least one Congo red derivative. In anembodiment, one or more of the targeting moieties 112 include[(trans,trans)-1-bromo-2,5-bis-(3-hydroxycarbonyl-4-hydroxy)styrylbenzene.

In an embodiment, a plurality of ferromagnetic microstructures 102includes two or more ferromagnetic microstructure sets. In anembodiment, at least one of the two or more ferromagnetic microstructuresets includes a different targeting moiety 112 from another of the twoor more ferromagnetic microstructure sets. In an embodiment, at leastone of the two or more ferromagnetic microstructure sets includes adifferent targeting moiety 112 configuration from another of the two ormore ferromagnetic microstructure sets 102.

In an embodiment, one or more of the ferromagnetic microstructures 102are configured to bind or interact with one or more targets within thecell. In an embodiment, one or more of the ferromagnetic microstructures102 are configured to enter into the cytoplasm of a cell.

In an embodiment, one or more of the ferromagnetic microstructures 102include one or more targeting moieties 112 that bind or interact withone or more intracellular targets. Examples of intracellular targetsinclude, but are not limited to, protein targets, lipid targets,oligonucleotide targets, and the like. Examples of intracellularproteins include, but are not limited to, enzymes (e.g.,oxidoreductases, transferases, hydrolases, lysases, isomerases,ligases), structural proteins (e.g., myosin, tubulin, intermediatefilaments, and actin), and the like. Examples of intracellular RNAsinclude, but are not limited to, messenger RNA, transfer RNA, ribosomalRNA, small nuclear RNA, small interfering RNA, microRNA, and the like.

In an embodiment, one or more of a plurality of ferromagneticmicrostructures 102 include one or more targeting moieties 112 directedat a genomic target. In an embodiment, one or more of a plurality offerromagnetic microstructures 102 include one or more genomic targetingmoieties. In an embodiment, one or more of the ferromagneticmicrostructures 102 are configured to selectively-target one or moregenomic targets. In an embodiment, the one or more genomic targetsinclude at least one deoxyribonucleic acid sequence. In an embodiment,the one or more genomic targets include at least one ribonucleic acidsequence. In an embodiment, the one or more genomic targets include atleast one oncogene. In an embodiment, the one or more genomic targetsinclude at least one chromosome translocation. In an embodiment, the oneor more genomic targets include at least one methylated deoxyribonucleicacid sequence. In an embodiment, the one or more genomic targets includeat least one methylated deoxyribonucleic acid sequence including amethylated cytosine. In an embodiment, the one or more genomic targetsinclude at least one methylated ribonucleic acid sequence. In anembodiment, the one or more genomic targets include at least onedeoxyribonucleic acid sequence including unmethylated cytosine.

In an embodiment, the one or more genomic targets include at least onesingle-nucleotide polymorphism. In an embodiment, the one or moregenomic targets include at least one of a somatic mutation, germlinemutation, chemically induced mutation, biologically induce mutation, oran environmentally induce mutation. In an embodiment, the one or moregenomic targets include at least one double stranded deoxyribonucleicacid sequence. In an embodiment, the one or more genomic targets includeat least one single stranded deoxyribonucleic acid sequence. In anembodiment, the one or more genomic targets include at least onemitochondrial deoxyribonucleic acid sequence. In an embodiment, the oneor more genomic targets include at least one of a point mutation, aninsertion of one or more nucleotides, or a deletion of one or morenucleotides. In an embodiment, one or more of the ferromagneticmicrostructures 102 include one or more antigen epitope targetingmoieties. In an embodiment, one or more of the ferromagneticmicrostructures 102 one or more antigen mimotopes targeting moieties. Inan embodiment, one or more of the ferromagnetic microstructures 102 atleast one single chain or a multiple chain antigen-recognition motif.

In an embodiment, one or more of a plurality of ferromagneticmicrostructures 102 include one or more targeting moieties 112 thattarget zinc finger-including proteins. In an embodiment, one or more ofthe ferromagnetic microstructures 102 one or more targeting moietiesthat target a zinc finger-including protein. In an embodiment, one ormore of the ferromagnetic microstructures 102 include one or moreproteins associated with a zinc finger motif, the one or more proteinsconfigured to bind a deoxyribonucleic acid sequence target. In anembodiment, one or more of the ferromagnetic microstructures 102 one ormore proteins associated with a zinc finger motif, the one or moreproteins configured to bind a ribonucleic acid sequence target. In anembodiment, one or more of the ferromagnetic microstructures 102 includeone or more proteins associated with a zinc finger motif, the one ormore proteins configured to target a deoxyribonucleic acid sequencetarget. In an embodiment, one or more of the ferromagneticmicrostructures 102 include one or more proteins associated with a zincfinger motif, the one or more proteins configured to target aribonucleic acid sequence target. In an embodiment, one or more of aplurality of ferromagnetic microstructures 102 include one or moretargeting moieties that target nucleic acid sequences in vivo. Forexample zinc finger domain-including proteins can be used to targetspecific DNA or RNA sequences. Examples of engineered and selected zincfinger domain-including proteins targeting promoter sequences or 5′untranslated regions of specific genes by binding in the major groove ofdouble stranded DNA are described in Blancafort et al, CombinatorialChemistry High Throughput Screening, vol. 11, pp. 146-158 (2008) andMoore et al, Briefings In Funct. Genom. Proteom., vol. 1, pp. 342-355(2003) which are incorporated by reference herein. In an embodiment, oneor more of a plurality of ferromagnetic microstructures 102 include oneor more targeting moieties 112 that target human chromosome in vivo. Inan embodiment, one or more of the ferromagnetic microstructures 102include one or more targeting moieties that target at least a portion ofa human chromosome in vivo.

One or more of the systems, devices, methods, and composition describedherein can be used alone or in combination with other diagnostic imagingtechniques and methodologies such as, for example, x-ray imaging,computed tomography (CT), ultrasound, magnetic resonance imaging (MRI),positron emission tomography (PET), single photon emission computedtomography (SPECT), gamma camera imaging, fluorescence tomography, orthe like.

In a non-limiting approach, systems, devices, methods, and compositiondescribed herein can include, among other things, one or more contrastagents for use in one or more diagnostic imaging technique. Anon-limiting approach includes imaging systems, devices, methods, andcompositions including, among other things, targeted ferromagneticmicrostructures and one or more imaging contrast agents.

For example, in an embodiment, a composition including ferromagneticmicrostructures 102 may incorporate at least one of contrast agents,radiopaques, or roentgenographic drugs for use in one or more diagnosticimaging technique. A non-limiting approach includes systems, devices,methods, and compositions including, among other things, one or moreimaging probes.

An aspect includes systems, devices, methods, and compositionsincluding, among other things, one or more imaging probes attached toone or more of the plurality of ferromagnetic microstructures 102. Anon-limiting approach includes systems, devices, methods, andcompositions including, among other things, one or more magneticresonance imaging contrast agents. In an embodiment, the one or moreimaging probes include at least one fluorescent agent. In an embodiment,the one or more imaging probes include at least one quantum dot. In anembodiment, the one or more imaging probes include at least oneradio-frequency identification transponder. In an embodiment, the one ormore imaging probes include at least one x-ray contrast agent. In anembodiment, the one or more imaging probes include at least onemolecular imaging probe. A non-limiting approach includes systems,devices, methods, and compositions including, among other things, one ormore contrast agents. Among imaging probes, examples include, but arenot limited to, fluorescent agents, molecular imaging probes, quantumdots, radio-frequency identification transponders (RFIDs), x-raycontrast agents, and the like.

Among contrast agents, radiopaques, or roentgenographic drugs used fordiagnostic x-ray imaging and computed tomography (CT), examples include,but are not limited to, barium sulfate and various iodine derivativesincluding diatrizoate meglumine, diatrizoate sodium, iodipamidemeglumine, diatrizoic acid, ethiodized oil, iodipamide, iodixanol,iohexol, iomeprol, iopamidol, iopanoic acid, iophendylate, iopromide,iothalamate meglumine, iothalamate sodium, iothalamic acid, ioversol,ioxaglate meglumaine, ioxaglate sodium, and the like.

Among contrast agents used for diagnostic ultrasound imaging, examplesinclude, but are not limited to, microbubbles of various compositions.Typically, microbubbles include a shell and a gas core. The shell may becomposed of albumin, galactose, lipid, or polymers. One example is abiodegradable shell of polybutyl-2 cyanoacrylate. The gas core may becomposed of air, nitrogen, or heavy gases like perfluorocarbon. Forexample, OPTISON (GE Healthcare) is an FDA approved microbubble forultrasound imaging composed of an albumin shell and an octafluoropropanegas core. Examples of other ultrasound contrast agents include, but arenot limited to, perfluorocytlbromide, perflutren lipid microspheres(DEFINITY; IMAGENT), sulfur hexafluoride (SONOVUE by Bracco), carbondioxide gas, perfluorobutane, MRX-801, SONOLYSIS (ImaRx Therapeutics),

TARGESTAR (Targeson), CARDIOSPHERE (POINT Biomedical), MAGNIFY(Acusphere, Inc), and the like.

Among contrast agents or enhancing agents used for diagnostic magneticresonance imaging, examples include, but are not limited to,paramagnetic and supramagnetic agents with one or more unpairedelectrons and typically include manganese, iron, or gadolinium in theirstructure. Examples of MRI contrast agents containing iron include, butare not limited to, ferumoxides (magnetite coated with dextran),ferumoxsil (magnetite coated with siloxane), ferumoxytol, ferumoxtran,ferucarbotran (RESOVIST), ferric chloride, ferric ammonium citrate, andthe like. Examples of MRI contrast agents containing gadolinium include,but are not limited to, gadopentetate dimeglumine (Gd-DTPA; MAGNEVIST),gadobutrol (GADOVIST), gadodiamide (Gd-DTPA-BMA; OMNISCAN), gadoteridol(PROHANCE), Gd-DOTA (DOTAREM), gadofosveset trisodium (VASOVIST),gadoversetamide (OPTIMARK), gadobenate dimeglumine (MULTIHANCE), and thelike. Examples of MRI contrast agents containing manganese include, butare not limited to, mangafodipir trisodium (TESLASCAN), EVP 1001-1, andthe like.

Among agents for diagnostic positron emission tomography (PET), singlephoton emission computed tomography (SPECT), or gamma camera imaging,examples include, but are not limited to, any of a number of agentscontaining one or more short-lived radioactive elements. They aretypically small organic molecules, but can also be macromolecules suchas peptides or antibodies. Radioisotopes may be incorporated into abiologically active molecule such as a metabolic tracer or a natural orsynthetic ligand or other binding agent targeted to a specific tissue orcellular location. For example, fluorine-18 fluorodeoxyglucose (FDG), aradioactive analog of glucose, is used to image highly metabolic solidtumors. Examples of other agents used for imaging or as tracers include,but are not limited to, compounds containing carbon-11, nitrogen-13,oxygen-15, and fluorine-18; salts of radioisotopes such as I-131 sodiumiodide, Tl-201 thallous chloride, Sr-89 strontium chloride; technetiumTc-99m; compounds containing iodine-123, iodine-124, iodine-125, andiodine-131; compounds containing indium-111 such as¹¹¹In-1,4,7,10-Tetraazacyclododecane-N,N′,N″,N′″-tetraacetic acid and¹¹¹In-Diethylenetriamine pentaacetic acid;¹⁷⁷Lu-[(R)-2-amino-3-(4-isothiocyanatophenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diamine-pentaaceticacid) (¹⁷⁷Lu-CHX-A″-DTPA), ⁶⁴Cu-DOTA, ⁸⁹Zr, ⁸⁶Y-DOTA, and the like.

Among agents used for diagnostic fluorescence imaging, examples include,but are not limited to, fluorescein (FITC), indocyanine green (ICG) andrhodamine B.

Examples of other fluorescent dyes for use in fluorescence imaginginclude, but are not limited to, a number of red and near infraredemitting fluorophores (600-1200 nm) including cyanine dyes such as Cy5,Cy5.5, and Cy7 (Amersham Biosciences, Piscataway, N.J., USA) or avariety of Alexa Fluor dyes such as Alexa Fluor 633, Alexa Fluor 635,Alexa Fluor 647, Alexa Fluor 660, Alexa Fluor 680, Alexa Fluor 700,Alexa Fluor 750 (Molecular Probes-Invitrogen, Carlsbad, Calif., USA;see, also, U.S. Patent Pub. No. 2005/0171434 (published Aug. 4, 2005)(the contents of which are incorporated herein by reference), and thelike.

Further examples of fluorophores include, but are not limited to,IRDye800, IRDye700, and IRDye680 (LI-COR, Lincoln, Nebr., USA), NIR-1and 1C5-OSu (Dejindo, Kumamotot, Japan), LaJolla Blue (Diatron, Miami,Fla., USA), FAR-Blue, FAR-Green One, and FAR-Green Two (Innosense,Giacosa, Italy), ADS 790-NS, ADS 821-NS (American Dye Source, Montreal,Calif.), NIAD-4 (ICx Technologies, Arlington, Va.), and the like.Further examples of fluorescing agents include BODIPY-FL, europium,green, yellow and red fluorescent proteins, luciferase, and the like.Quantum dots of various emission/excitation properties may be used forfluorescence imaging. See, e.g., Jaiswal, et al. Nature Biotech.21:47-51 (2003) (the contents of which are incorporated herein byreference).

In an embodiment, one or more of the ferromagnetic microstructures 102include one or more binding agents. For example, one or moreferromagnetic microstructures 102 may incorporate one or more bindingagents configured to bind at least one of an imaging probe, at least oneof a contrast agent or both. Among the one or more binding agents,examples include, but are not limited to, antibodies or fragmentsthereof, oligonucleotide or peptide based aptamers, receptors or partsthereof, artificial binding substrates formed by molecular imprinting,biomolecules, mutant or genetically engineered proteins or peptides,further details of which have been described herein.

In an embodiment, one or more of the ferromagnetic microstructures 102include one of a ligand-receptor binding pair. In an embodiment, atleast one of the ferromagnetic microstructures 102 includes one of aligand-receptor binding pair. The one of a ligand-receptor binding pairis configured to bind to the other of the ligand-receptor binding pairto form the ligand-receptor binding pair. The other of theligand-receptor binding pair is further associated with at least one ofan imaging agent, at least one of a contrast agent, or both. Theformation of the ligand-receptor binding pair links the ferromagneticmicrostructures 102 to at least one of an imaging agent, at least one ofa contrast agent, or both. Among ligand-receptor binding pairs, examplesinclude, but are not limited to, antigen-antibody binding pairs,biotin-streptavidin binding pairs, biotin-avidin binding pairs,substrate-enzyme binding pairs, protein-protein binding pairs,protein-peptide binding pairs, primary antibody-secondary antibodybinding pairs, sense oligonucleotide-antisense oligonucleotide bindingpairs, aptamer-target binding pairs, artificial binding substrate-targetbinding pairs, peptide-nucleic acid (PNA)-DNA or RNA binding pairs.

Several technologies and methodologies can be use to assemble, link,bind, associate, or the like the various ligand-receptor binding pairs,ferromagnetic microstructures 102, contrast agents, imaging proves, orthe like. In an embodiment, the ligand-receptor binding pair is anazide-alkyne binding pair that is capable of undergoing a cycloadditionchemical reaction in an in vivo biological system to form a covalentlinkage. See, e.g., Baskin, et al., Proc. Natl. Acad. Sci. USA104:16793-16797 (2007) (the contents of which are incorporated herein byreference).

In an embodiment, the formation of the ligand-receptor binding pair isperformed after administration of the ferromagnetic microstructures 102to a biological subject. The ferromagnetic microstructures 102 includingone of a ligand-receptor binding pair can be administered to abiological subject before or after administration of the imaging probeor contrast agent including the other of the ligand-receptor bindingpair. For example, the ferromagnetic microstructures 102 including oneof a ligand-receptor binding pair and at least one targeting moiety canbe administered to a biological subject and accumulated in one or morecell or tissue type based on the specificity of the targeting moiety. Ata later time, at least one imaging agent or contrast agent including theother of the ligand-receptor binding pair is administered and binds tothe one of the ligand-receptor binding pair of the ferromagneticmicrostructures 102 previously accumulated in one or more cells ortissue types. Alternatively, the ferromagnetic microstructures 102 andimaging probe or contrast agent including one or the other of theligand-receptor bind pair can be administered to a biological subjectseparately but essentially concurrently. In an embodiment, the formationof the ligand-receptor binding pair to link the ferromagneticmicrostructures 102 and at least one imaging probe, contrast agent, orboth can be performed prior to administering the ferromagneticmicrostructures 102 to a biological subject.

In an embodiment, one or more of the ferromagnetic microstructures 102include one or more binding agents attached thereof. In an embodiment,one or more of the binding agents are configured to bind to at least oneimaging probe. In an embodiment, one or more of the binding agents areconfigured to bind to at least one imaging probe in vivo. In anembodiment, one or more of the ferromagnetic microstructures 102 includeone of a ligand-receptor binding pair attached thereof

In an embodiment, the one of the ligand-receptor binding pair isconfigured to bind with an imaging probe including the other of theligand-receptor binding pair. In an embodiment, the one of theligand-receptor binding pair is configured to bind, in vivo, with animaging probe including the other of the ligand-receptor binding pair.In an embodiment, one or more of the ferromagnetic microstructures 102include one or more binding agents attached thereof. In an embodiment,one or more of the binding agents are configured to bind to at least onecontrast agent. In an embodiment, one or more of the binding agents areconfigured to bind to at least one contrast agent in vivo. In anembodiment, one or more of the ferromagnetic microstructures 102 includeone of a ligand-receptor binding pair attached thereof. In anembodiment, the one of the ligand-receptor binding pair is configured tobind with an contrast agent including the other of the ligand-receptorbinding pair. In an embodiment, the one of the ligand-receptor bindingpair is configured to bind, in vivo, with an contrast agent includingthe other of the ligand-receptor binding pair.

In general, any of a number of homobifunctional, heterofunctional, orphotoreactive cross-linking agents can be used to link the targetingmoiety 112 to the ferromagnetic microstructure 102. The targeting moiety112 can be linked to the ferromagnetic microstructure 102 through, forexample, amine groups, sulfhydryl groups, carbohydrate groups, or acombination thereof. Examples of homobifunctional cross-linkers include,but are not limited to, primary amine/primary amine linkers such asBSOCES ((bis(2-[succinimidooxy-carbonyloxy]ethyl)sulfone), DMS (dimethylsuberimidate), DMP (dimethyl pimelimidate), DMA (dimethyl adipimidate),DSS (disuccinimidyl suberate), DST (disuccinimidyl tartate), Sulfo DST(sulfodisuccinimidyl tartate), DSP (dithiobis(succinimidyl propionate),DTSSP (3,3′-dithiobis(succinimidyl propionate), EGS (ethylene glycolbis(succinimidyl succinate)) and sulfhydryl/sulfhydryl linkers such asDPDPB (1,4-di-(3′-[2′pyridyldithio]-propionamido)butane). Examples ofheterofunctional cross-linkers include, but are not limited to, primaryamine/sulfhydryl linkers such as MBS(m-maleimidobenzoyl-N-hydroxysuccinimide ester), Sulfo MBS(m-maleimidobenzoyl-N-hydroxysulfosuccinimide), GMBS(N-gamma-maleimidobutyryl-oxysuccinimide ester), Sulfo GMBS(N-gamma-maleimidobutyryloxysulfosuccinimide ester), EMCS(N-(epsilon-maleimidocaproyloxy) succinimide ester), Sulfo EMCS(N-(epsilon-maleimidocaproyloxy)sulfo succinimide), SIAB(N-succinimidyl(4-iodoacetyl)aminobenzoate), SMCC (succinimidyl4-(N-maleimidomethyl)cyclohexane-1-carboxylate), SMPB (succinimidyl4-(rho-maleimidophenyl)butyrate), Sulfo SIAB(N-sulfosuccinimidyl(4-iodoacetyl)aminobenzoate), Sulfo SMCC(sulfosuccinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate),Sulfo SMPB (sulfosuccinimidyl 4-(rho-maleimidophenyl)butyrate), andMAL-PEG-NHS (maleimide PEG N-hydroxysuccinimide ester);sulfhydryl/hydroxyl linkers such as PMPI(N-rho-maleimidophenyl)isocyanate; sulfhydryl/carbohydrate linkers suchas EMCH (N-(epsilon-maleimidocaproic acid)hydrazide); and amine/carboxyllinkers such as EDC (1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride).

A targeting moiety 102 can be linked to a ferromagnetic microstucture102 through an azide-alkyne mediated linkage. The copper-catalyzedazide-alkyne cycloaddition is a 1,3-dipolar cycloaddition between anazide and a terminal alkyne to form a triazole (see, e.g., Heine et al.,Pharm. Res. 25:2216-2230, 2008; Ming, et al., Nucleic Acids Symp. Ser.(Oxf). 52:471-472, 2008; Van Dongen, et al., Bioconjugate Chem.20:20-23, 2009; Godeau, et al, J. Med. Chem. 51:4374-4376, 2008, whichare incorporated herein by reference). A copper-free cycloadditionreaction has also been described for use in living cells (see, e.g.,Baskin et al., Proc. Natl. Acad. Sci., USA. 104:16793-16797, 2007, whichis incorporated herein by reference). To link one or more components,one component is derivatized with azide while the other component isderivatized with alkyne and snapped together using “click chemistry”.For example, the targeting moiety and the ferromagnetic microstructurescan be functionalized with azide and/or alkyne for use in “clickchemistry” reactions and “snapped” together.

Alternatively, ferromagnetic microstructures 102 can be tethered to aprotein transduction domain (PTD) to facilitate entry of theferromagnetic microstructure in a cell and/or across the blood brainbarrier. Examples of PTDs include the human immunodeficiency virus type1 (HIV-1) transactivator of transcription (Tat), antennapedia peptide,herpes simplex virus VP22, buforin, lipid membrane translocatingpeptide, mastoparan, and transportan. In one aspect, all or part of the86 amino acid long Tat PTD may be added to the ferromagneticmicrostructures through primary amines associated with the peptideand/or the functionalized ferromagnetic microstructures using themethods described herein (also see, e.g., Santra, et al., Chem. Commun.24:2810-2811, 2004, which is incorporated herein by reference).

Under certain conditions, the ferromagnetic microstructures 102 can beactively taken up by a cell through the process of endocytosis wherebycells absorb extracellular material by engulfing the material with theircell membrane. The engulfed material is contained in small vesicles thatpinch off from the plasma membrane, enter the cytoplasm and fuse withother intracellular vesicles, e.g., endosomes or lysosomes. Theferromagnetic microstructure 102 can be released from endosomes by anumber of mechanisms. In an aspect, artificial acceleration of endosomalrelease may be achieved by photo-excitation of fluorescent probesassociated with the engulfed material (see, e.g., Matsushita, et al.,FEBS Lett. 572:221-226, 2004, which is incorporated herein byreference). Alternatively, the ferromagnetic microstructure may includea pH sensitive element that is activated in the low pH environment ofthe endosome. For example, all or part of the influenza virushemagglutinin-2 subunit (HA-2), a pH-dependent fusogenic peptide thatinduces lysis of membranes at low pH, may be used to induce efficientrelease of encapsulated material from cellular endosomes (see, e.g.,Yoshikawa, et al., J. Mol.

Biol. 380:777-782, 2008, which is incorporated herein by reference).

The ferromagnetic microstructure 102 may enter the cell by passingdirectly through the cell membrane and into the cytoplasm. In thisinstance, the tubular nanostructure may include moieties on the surfaceof the microstructure that confers direct passage through the lipidbilayer, e.g., an amphipathic striated surface coating. For example, thedeposition of a hydrophilic-hydrophobic striated pattern of molecules,e.g., the anionic ligand 11-mercapto-1-undecanesulphonate (MUS) and thehydrophobic ligand 1-octanethiol (OT) on the surface of microstructurescan facilitate direct passage of the microstructure across cellularmembranes (see, e.g., Verma, et al., Nature Materials 7:588-95, 2008,which is incorporated herein by reference). Further examples oftechniques and methodologies for targeting ferromagnetic microstructures102 may be found in, for example, the following documents (the contentsof which are incorporated herein by reference): Peng et al., TargetedMagnetic Iron Oxide Nanoparticles for Tumor Imaging and Therapy,International journal of nanomedicine 3(3):311-21 (2008); Selim et al.,Surface Modification of Magnetite Nanoparticles Using Lactobionic Acidand Their Interaction With Hepatocytes, Biomaterials, 28(4):710-6(2007); Serda et al., Targeting and Cellular Trafficking of MagneticNanoparticles for Prostate Cancer Imaging, Mol Imaging. 6(4):277-88(2007); Quantum dot-trastuzumab [QT], Molecular Imaging and ContrastAgent Database NIH, 1-5 (2007)(http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=micad&part=Qd-Trastuzumab);Chopra, A., Monoclonal antibody against antigen A7 coupled toferromagnetic lignosite particles [A7-FML], Molecular Imaging andContrast Agent Database NIH, 1-4 (2008)(http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=micad&part=A7-FMLMRI);and U.S. Patent Publication No. 2009/0029392 (published Jan. 29, 2009.

In an embodiment, one or more surfaces of a ferromagnetic microstructure102 are functionalized with one or more functional groups. Varioustechnologies and methodologies can be use to modify a surfaces of aferromagnetic microstructure 102 so that a plurality of functionalgroups is present thereon. The manner of treatment is dependent on, forexample, the nature of the chemical compound to be synthesized and thenature and composition of the surface. See, e.g., U.S. PatentPublication No. 2007/0078376 (published Apr. 5, 2007) (the contents ofwhich is incorporated herein by reference). In some embodiments, thesurface may include functional groups selected to impart one or more ofproperties to the surface including nonpolar, hydrophilic, hydrophobic,organophilic, lipophilic, lipophobic, acidic, basic, neutral,properties, increased or decreased permeability, and the like, and/orcombinations thereof. For example, one or more of the ferromagneticmicrostructures 102 can include one or more functional groups thatimpart or more functionalities (e.g., charge functionally, hydrophobicfunctionally, hydrophilic functionally, chemically reactivefunctionally, organo functionally, water-wettable functionally, or thelike) to the ferromagnetic microstructures 102.

In an embodiment, one or more of the ferromagnetic microstructures 102include one or more functional groups that are useful to attach (e.g.,link, bind, conjugate, complex, associate, or the like) a targetingmoiety 112 to the ferromagnetic microstructure 102. In an embodiment,one or more of the ferromagnetic microstructures 102 include one or morefunctional groups that impart one or more properties (e.g., chemicalproperties, chemically reactive properties, association properties,electrostatic interaction properties, bonding properties, biocompatibleproperties, or the like) to the ferromagnetic microstructures 102including acidic, basic, hydrophilic, hydrophobic, lipophilic,lipophobic, neutral, nonpolar, organophilic, properties, increased ordecreased permeability, and the like, and combinations thereof.

Among functional groups, examples include, but are not limited tochemical groups that confer special properties or particular functionsto the ferromagnetic microstructures 102. Among chemical groups,examples include, but not limited to, an atom, an arrangement of atoms,an associated group of atoms, molecules, moieties, and that like, thatconfer certain characteristic properties on the ferromagneticmicrostructures 102 including the functional groups. Further examples offunctional groups include, charge functional groups, hydrophobicfunctional groups, hydrophilic functional groups, chemically reactivefunctional groups, organofunctional group, water-wettable groups,bio-compatible functional groups, and the like. Further examples offunction groups include nonpolar functional groups, hydrophilicfunctional groups, hydrophobic functional groups, organophilicfunctional groups, lipophilic functional groups, lipophobic functionalgroups, acidic functional groups, basic functional groups, neutralfunctional groups, and the like. In an embodiment, the functional groupsmay impart one or more properties to a surface of the ferromagneticmicrostructures 102 including, for example, nonpolar, hydrophilic,hydrophobic, organophilic, lipophilic, lipophobic, acidic, basic,neutral, properties, increased or decreased permeability, and the like,and/or combinations thereof. Further examples of function groups includealcohols, hydroxyls, amines, aldehydes, dyes, ketones, cabonyls, thiols,phosphates, carboxyls, caboxilyic acids, carboxylates, proteins, lipids,polysaccharides, pharmaceuticals, metals, —CO—R, —NH₃ ⁺, —COOH, —COO⁻,—SO₃, —CH₂N⁺(CH₃)₃, —(CH₂)_(m)CH₃, —C((CH₂)_(m)CF₃)₃, —CH₂N(C₂H₅)₂,—NH₂, —(CH₂)_(m)COOH, —(OCH₂CH₂)_(m)CH₃, —SiOH, —OH, and the like.

In an embodiment, one or more of the ferromagnetic microstructures 102include one or more immobilized targeting moieties 112. In anembodiment, one or more of the ferromagnetic microstructures 102 includea siloxane-scaffold on one or more surfaces. In an embodiment, thesiloxane-scaffold is configured to immobilize one or more targetingmoieties 112 to a surface of the ferromagnetic microstructures 102. Seee.g., Dow Corning, Guide to Silane Solutions, (2005)(http://www.dowcorning.com/content/publishedlit/SILANE-GUIDE.pdf). In anembodiment, one or more of the plurality of ferromagneticmicrostructures 102 include, but are not limited to, a siloxane coating,a silane coating, or the like.

In an embodiment, a composition includes one or more ferromagneticmicrostructures 102 having an external surface 110 and an internalsurface 104, the internal surface 104 defining a void 106, the void 106being accessible to a biological sample. In an embodiment, one or moreferromagnetic microstructures 102 are configured to generate atime-invariant magnetic field 108 within at least a portion of the void.In an embodiment, one or more targeting moieties 112 are attached to atleast one of the one or more of the ferromagnetic microstructures 102.

In an embodiment, at least one of the internal surface 104 or theexternal surface 110 includes one or more functional groups. In anembodiment, the one or more functional groups include at least one of abio-compatible functional group, a charge functional group, a chemicallyreactive functional group, a hydrophilic functional group, a hydrophobicfunctional group, or an organofunctional group. In an embodiment, eitherthe internal surface 104 or the external surface 110, or both may bemodified to include one or more functional groups. In an embodiment, atleast a portion of the internal surface 104, the external surface 110,or both may be modified to include one or more functional groups. In anembodiment, at least the interior surface 104 of one or more of theferromagnetic microstructures 102 is modified with a sufficient amountof one or more functional groups.

In an embodiment, a functional groups may include a binding group (e.g.,coupling agents, and the like), a linking group (e.g., spacer groups,organic spacer groups, and the like), and/or a matrix-forming group thataid in, for example, binding the functional groups to the internalsurface 104, the external surface 110, or both, or aid in providing thedesired functionality. Among binding groups, examples include, but notlimited to, acrylates, alkoxysilanes, alkyl thiols, arenes, azidos,carboxylates, chlorosilanes, alkoxysilanes, acetocysilanes, silazanes,disilazanes, disulfides, epoxides, esters, hydrosilyl, isocyanates. andphosphoamidites, isonitriles, methacrylates, nitrenes, nitriles,quinones, silanes, sulfhydryls, thiols, vinyl groups, and the like.

Among linking groups, examples include, but not limited to, dendrimers,polymers, hydrophilic polymers, hyperbranched polymers, poly(aminoacids), polyacrylamides, polyacrylates, polyethylene glycols,polyethylenimines, polymethacrylates, polyphosphazenes, polysaccharides,polysiloxanes, polystyrenes, polyurethanes, propylene's, proteins,telechelic block copolymers, and the like.

Among matrix-forming groups, examples include, but not limited to,dendrimer polyamine polymers, bovine serum albumin, casein, glycolipids,lipids, heparins, glycosaminoglycans, muscin, surfactants,polyoxyethylene-based surface-active substances (e.g.,polyoxyethlene-polyoxypropylene copolymers, polyoxyethylene 12 tridecylether, polyoxyethylene 18 tridecyl ether, polyoxyethylene 6 tridecylether, polyoxyethylene sorbitan tetraoleate, polyoxyethylene sorbitolhexaoleate, and the like) polyethylene glycols, polysaccharides, serumdilutions, and the like.

An aspect includes systems, devices, methods, and compositionsincluding, among other things, ferromagnetic microstructures 102configured to allow selective-accessible to one or more internal surfacedefined voids 106. A non-limiting approach includes systems, devices,methods, and compositions including, among other things, ferromagneticmicrostructures 102 having an interior that is selectively accessible toa biological sample. A non-limiting approach includes systems, devices,methods, and composition including, among other things, one or more ofthe ferromagnetic microstructure sets configured to allow an in vivobiological sample selective-access to one or more internal voids 106. Anon-limiting approach includes systems, devices, methods, andcompositions including, among other things, targeted ferromagneticmicrostructures having an interior that is selectively accessible to abiological sample. In an embodiment, the targeted ferromagneticmicrostructures 102 include one or more targeting moieties 112 attachedthereof. In an embodiment, one or more of the ferromagneticmicrostructure sets include one or more ferromagnetic microstructuresincluding one or more bound targeting moieties 112.

Referring to FIGS. 2A and 2B, in an embodiment, one or more of theferromagnetic microstructure sets 200 include, but are not limited to,an ion selective selectively-accessible internal void 106 a. In anembodiment, one or more of the ferromagnetic microstructure sets 200include, but are not limited to, a molecule selectiveselectively-accessible internal void 106 a.

In an embodiment, one or more of the plurality of ferromagneticmicrostructures include, but are not limited to, a first internalsurface 104 defining a void 106 a configured to beselectively-accessible to a biological sample. In an embodiment, one ormore of the plurality of ferromagnetic microstructures include asufficient amount of one or more ferromagnetic materials to generate atime-invariant magnetic field 108 within the selectively-accessible void106 a. In an embodiment, one or more of the plurality of ferromagneticmicrostructures 102 include, but are not limited to, a coating 202 thatselectively allows access to the defined void 106. In an embodiment, oneor more of the plurality of ferromagnetic microstructures 102 include,but are not limited to, one or more pH-sensitive polymer coatingsconfigured to selectively allow access to the defined void 106. In anembodiment, one or more of the plurality of ferromagneticmicrostructures 102 include, but are not limited to, a membrane 204 thatselectively allows access to the defined void 106. In an embodiment, oneor more of the plurality of ferromagnetic microstructures 102 include,but are not limited to, a degradable membrane that selectively allowsaccess to the defined void 106.

In an embodiment, one or more of the plurality of ferromagneticmicrostructures 102 include, but are not limited to, a component 206that selectively allows access to the defined void 106. In anembodiment, one or more of the plurality of ferromagneticmicrostructures 102 include, but are not limited to, a degradablecomponent that selectively allows access to the defined void 106. In anembodiment, one or more of the plurality of ferromagneticmicrostructures 102 include, but are not limited to, a pH sensitivedegradable component that selectively allows access to the defined void106. In an embodiment, one or more of the plurality of ferromagneticmicrostructures 102 include, but are not limited to, a pH degradablecomponent configured to selectively allow access to the defined void106. In an embodiment, one or more of the plurality of ferromagneticmicrostructures 102 include, but are not limited to, a photodegradablecomponent that selectively allows access to the defined void 106.

In an embodiment, one or more of the plurality of ferromagneticmicrostructures 102 include, but are not limited to, a degradablepolymeric substrate that selectively allows access to the defined void106. In an embodiment, one or more of the plurality of ferromagneticmicrostructures 102 include, but are not limited to, a shape-memorycomponent including one or more shape-memory polymers. See, e.g.,Farokhzad et al., Drug Delivery Systems in Urology-Getting “Smarter”,Urology 68(3); 463-469 (2006) (the contents of which are incorporatedherein by reference).

In an embodiment, one or more of the plurality of ferromagneticmicrostructures 102 include, but are not limited to, a biodegradablepolymer shape-memory component. In an embodiment, one or more of theplurality of ferromagnetic microstructures 102 include, but are notlimited to, a biodegradable polymer component. In an embodiment, one ormore of the plurality of ferromagnetic microstructures 102 include, butare not limited to, an ion-selective component that selectively allowsaccess to the defined void 106. In an embodiment, one or more of theplurality of ferromagnetic microstructures 102 include, but are notlimited to, a charge-selective component that selectively allows accessto the defined void 106. In an embodiment, one or more of the pluralityof ferromagnetic microstructures 102 include, but are not limited to, asize-selective component that selectively allows access to the definedvoid 106. In an embodiment, one or more of the plurality offerromagnetic microstructures 102 include, but are not limited to, asize-exclusion component that selectively restricts access to thedefined void 106.

Referring to FIGS. 3A, 3B, and 3C, a non-limiting approach includessystems, devices, methods, and compositions including, among otherthings, ferromagnetic microstructures 102 that are incorporated in amatrix material 300 that that selectively allows access to an interiorof the ferromagnetic microstructures 102. A non-limiting approachincludes systems, devices, methods, and compositions including, amongother things, ferromagnetic microstructures 102 that are oriented andencapsulated in a matrix material 300 that that selectively allowsaccess to an interior of the ferromagnetic microstructures 102. Drypressing, quickly solidifying, annealing, or the like the matrixmaterial 300 while applying magnetic field to orient the ferromagneticmicrostructures 102. Other techniques and methodologies for fabricatingferromagnetic microstructures 102 that are oriented and encapsulated ina matrix material 300 include those used in creating structures such as,for example, aerogels, hydrogels, nanogels, sol-gels, xerogels, or thelike. In an embodiment, ferromagnetic microstructures 102 that areincorporated in a matrix can be sintered, cross-linked, adhered, orjoined otherwise to for larger structures. In an embodiment, individualferromagnetic microstructures 102 can be coated and subsequentlysintered, cross-linked, adhered, or joined otherwise to for largerstructures.

In an embodiment, individual ferromagnetic microstructures 102 can besintered to form ferromagnetic microstructures 102 of varying sizes anddimension. In an embodiment, individual ferromagnetic microstructures102 can be sintered in the presence of a magnetic field to formferromagnetic microstructures 102 of varying magnetic properties.

FIG. 4 shows a system 400 in which one or more methodologies ortechnologies may be implemented. In an embodiment, the system 400includes one or more radio frequency (RF) transmitter assemblies 402including at least one RF transmitters configured to generate an RFsignal. In an embodiment, RF pulses delivered by the RF transmitterassembly 402 excite a region of interest within a biological subject.See, e.g., the following documents (the contents of which areincorporated herein by reference): U.S. Pat. No. 5,175,499 (issued Dec.29, 1992), U.S. Pat. No. 6,275,722 (issued Aug. 14, 2001), U.S. Pat. No.6,873,153 (issued Mar. 29, 2005), U.S. Pat. No. 6,879,160 (issued Apr.12, 2005), U.S. Pat. No. 6,977,503 (issued Dec. 20, 2005), U.S. Pat. No.7,075,302 (issued Jul. 11, 2006), U.S. Pat. No. 7,096,057 (issued Aug.22, 2006), U.S. Pat. No. 7,095,230 (issued Aug. 22, 2006), U.S. Pat. No.7,309,986 (issued Dec. 18, 2007), U.S. Pat. No. 7,418,289 (issued Aug.26, 2008), U.S. Pat. No. 7,483,732 (issued Jan. 27, 2009), and U.S. Pat.No. 7,495,439 (issued Feb. 24, 2009); U.S. Patent Publ. Nos.2007/0194788 (published Aug. 23, 2007), and 2008/0306377 (Dec. 11,2008), 2009/0015256 (published Jan. 15, 2009); WO 2005/101045 (publishedOct. 27, 2005), WO 2009/027973 (published Mar. 5, 2009), WO 2009/029880(published Mar. 5, 2009), and WO 2009/029896 (published Mar. 5, 2009)

In an embodiment, an RF transmitter assembly 402 can include one or moreof controllers, digital attenuators, digital-to-analog converters,amplifiers (e.g., power amplifiers, RF amplifiers, or the like), RFsynthesizer, signal conditioning amplifiers, transmitting coils (e.g.,RF transmitting coils, or the like), and waveform generators. In anembodiment, the system 400 includes at least one coil configured togenerate one or more RF pulses based on, for example, a control input,output, a command, or a response. In an embodiment, an RF transmitteroperating in conjunction with, for example, an RF oscillator, generatesan RF signal. An RF amplifier amplifies the RF signal that drives an RFtransmitter coil that in turn provides RF pulses that excite the nuclearmagnetization of non-zero spin nuclei in a region of interest. In anembodiment, an RF transmitted coil including a transmit/receive switchcan be used as a receiver coil.

In an embodiment, the system 400 includes one or more RF receiverassemblies 404 including at least one RF receiver configured to acquireRF information emitted by the biological sample. In an embodiment, an RFreceiver assembly 402 can include one or more of analog-to-digitalconverters, matching networks, oscillators, power amplifiers, RF receivecoils, RF synthesizers, or signal filters. In an embodiment, the system400 includes one or more RF transceivers 406 configured to generate RFexcitation pulses that interacts with, for example, in vivo targetnon-zero spin nuclei.

In an embodiment, the system 400 includes one or more magnetic resonancedetectors 408. Examples of magnetic resonance detectors can be found in,for example, the following documents (the contents of which areincorporated herein by reference): U.S. Pat. No. 7,271,589 (issued Sept.18, 2007) and U.S. Pat. No. 7,258,734 (issued Arp. 15, 2008); U.S.Patent Publ. Nos. 2009/0015256 (published Jan. 15, 2009), 2007/0194788(published Aug. 23, 2007), and 2007/0020701 (published Jan. 25, 2007).In an embodiment, the one or more magnetic resonance detectors 408 areconfigured to detect (e.g., assess, calculate, evaluate, determine,gauge, measure, monitor, quantify, resolve, sense, or the like) emittednuclear magnetic information (e.g., RF information, an RF signal, anuclear magnetic resonance, an in vivo magnetic resonance eventgenerated by nuclear magnetic resonance detectable nuclei, or the like)and to generate a response based on the detected e nuclear magneticinformation.

In an embodiment, the response includes al least one of a display, avisual representation (e.g., a plot, a display, a spectrum, a visualdepiction representative of the detected information, a visual depictionrepresentative of a physical object (e.g., a ferromagneticmicrostructure, a contrast agent, tissue, an indwelling implant, fat,muscle, bone, non-zero spin nuclei, a biological fluid component, or thelike) a visual display, a visual display of at least one spectralparameter, and the like. In an embodiment, the response includes alleast one of a visual representation, an audio representation (e.g., analarm, an audio waveform representation of a magnetic resonance event,or the like), or a tactile representation (e.g., a tactile diagram, atactile display, a tactile graph, a tactile interactive depiction, atactile model (e.g., a multidimensional model of a physical object or amagnetic resonance event, or the like), a tactile pattern (e.g., arefreshable Braille display), a tactile-audio display, a tactile-audiograph, or the like). In an embodiment, the response includes an output,a response signal, a display, a data array, or a spectral plot. In anembodiment, the response includes one or more images associated with atleast one of a spatial distribution of T₁ relaxation time information ora spatial distribution of T₂ relaxation time information. In anembodiment, the response includes a visual representation indicative ofa parameter associated with one or more ferromagnetic microstructures.

In an embodiment, the system 400 includes one or more gradient coilassemblies 410 including at least one gradient coil configured tospatially encode a position of NMR active nuclei by, for example,varying the magnetic field linearly across an imaging volume. The Larmorfrequency of the NMR active nuclei will then vary as a function ofposition in the x, y and z-axes. In an embodiment, the system 400includes one or more RF coil assemblies 412.

The system 400 can be used alone or in combination with other diagnosticimaging techniques and methodologies such as, for example, x-rayimaging, computed tomography (CT), ultrasound, magnetic resonanceimaging (MRD, positron emission tomography (PET), single photon emissioncomputed tomography (SPECT), gamma camera imaging, fluorescencetomography, or the like. In an embodiment, the system 400 includes oneor more contrast agent detection assemblies 414.

In an embodiment, the system 400 includes means for affecting an in vivomagnetic resonance relaxation process associated with a biologicalsample, in the absence of an externally generated magnetic field. Themeans for affecting an in vivo magnetic resonance relaxation processincludes a 102. The means for affecting an in vivo magnetic resonancerelaxation process can further include for example, but not limited, toelectrical control components, electromechanical control components,software control components, firmware control components, circuitrycontrol components, or other control components, or combinationsthereof. Examples of circuitry control components can be found, amongother things, in U.S. Pat. No. 7,236,821 (issued Jun. 26, 2001) (thecontents of which are incorporated herein by reference).

In an embodiment, the system 400 can includes one or more components 416(e.g., hardware, software, firmware, mechanical systems,electro-mechanical system, or the like) associated with other diagnosticimaging techniques and methodologies such as, for example, x-rayimaging, computed tomography (CT), ultrasound, magnetic resonanceimaging (MRI), positron emission tomography (PET), single photonemission computed tomography (SPECT), gamma camera imaging, fluorescencetomography, or the like.

In a general sense, the various aspects described herein (which can beimplemented, individually and/or collectively, by a wide range ofhardware, software, firmware, and/or any combination thereof) can beviewed as being composed of various types of “electrical circuitry.”Consequently, as used herein electrical circuitry or electrical controlcomponent circuitry includes, but is not limited to, electricalcircuitry having at least one discrete electrical circuit, electricalcircuitry having at least one integrated circuit, electrical circuitryhaving at least one application specific integrated circuit, electricalcircuitry forming a general purpose computing device configured by acomputer program (e.g., a general purpose computer configured by acomputer program which at least partially carries out processes and/ordevices described herein, or a microprocessor configured by a computerprogram which at least partially carries out processes and/or devicesdescribed herein), electrical circuitry forming a memory device (e.g.,forms of memory (e.g., random access, flash, read only, etc.)), and/orelectrical circuitry forming a communications device (e.g., a modem,communications switch, optical-electrical equipment, etc.). The subjectmatter described herein may be implemented in an analog or digitalfashion or some combination thereof.

Consequently, as used herein electro-mechanical system includes, but isnot limited to, electrical circuitry operably coupled with a transducer(e.g., an actuator, a motor, a piezoelectric crystal, a Micro ElectroMechanical System (MEMS), etc.), electrical circuitry having at leastone discrete electrical circuit, electrical circuitry having at leastone integrated circuit, electrical circuitry having at least oneapplication specific integrated circuit, electrical circuitry forming ageneral purpose computing device configured by a computer program (e.g.,a general purpose computer configured by a computer program which atleast partially carries out processes and/or devices described herein,or a microprocessor configured by a computer program which at leastpartially carries out processes and/or devices described herein),electrical circuitry forming a memory device (e.g., forms of memory(e.g., random access, flash, read only, etc.)), electrical circuitryforming a communications device (e.g., a modem, communications switch,optical-electrical equipment, etc.), and/or any non-electrical analogthereto, such as optical or other analogs. Examples ofelectro-mechanical systems include, but are not limited to, a variety ofconsumer electronics systems, medical devices, as well as other systemssuch as motorized transport systems, factory automation systems,security systems, and/or communication/computing systems. The term,electro-mechanical, as used herein is not necessarily limited to asystem that has both electrical and mechanical actuation except ascontext may dictate otherwise.

In an embodiment, the means for affecting an in vivo magnetic resonancerelaxation process can include a nuclear magnetic resonance imagingcomposition including, but is not limited to, one or more ferromagneticmicrostructures 102. In an embodiment, one or more of the ferromagneticmicrostructures 102 include, but are not limited to, at least a firstinternal surface 104 defining a void 106 accessible to a biologicalsample. In an embodiment, one or more of the ferromagneticmicrostructures 102 include at least an outer surface 110. In anembodiment, the means for affecting an in vivo magnetic resonancerelaxation process can further include an RF transmitter assembly 402including one or more of controllers, digital attenuators,digital-to-analog converters, amplifiers (e.g., power amplifiers, RFamplifiers, or the like), RF synthesizer, signal conditioningamplifiers, transmitting coils (e.g., RF transmitting coils, or thelike), and waveform generators. In an embodiment, the means foraffecting an in vivo magnetic resonance relaxation process can furtherinclude one or more RF receiver assemblies 404 including at least one RFreceiver configured to acquire RF information emitted by the biologicalsample. In an embodiment, an RF receiver assembly 402 can include one ormore of analog-to-digital converters, matching networks, oscillators,power amplifiers, RF receive coils, RF synthesizers, or signal filters.In an embodiment, the system 400 includes one or more RF transceivers406 configured to generate RF excitation pulses that interacts with, forexample, in vivo target non-zero spin nuclei.

In an embodiment, one or more of the ferromagnetic microstructures 102are configured to generate one or more time-invariant magnetic fields108 within at least a portion of the void 106. In an embodiment, thetime-invariant magnetic field 108 within the void 106 includes asubstantially homogeneous polarizing magnetic field region. In anembodiment, at least a first internal surface 104 of at least one of theone or more ferromagnetic microstructures 102 includes one or moretargeting moieties 112. In an embodiment, at least an outer surface 110of at least one of the one or more ferromagnetic microstructures 102includes one or more targeting moieties 112. In an embodiment, amajority of the one or more targeting moieties 112 is localize to aportion of the void 106 including a time-invariant magnetic field 108.

In an embodiment, the means for affecting an in vivo magnetic resonancerelaxation process can include circuitry for acquiring informationassociated with an in vivo magnetic resonance event generated by nuclearmagnetic resonance detectable nuclei received in one or more voids 106of a plurality of ferromagnetic microstructures configured to generate astatic magnetic field within the void 106.

In an embodiment, the means for affecting an in vivo magnetic resonancerelaxation process can include at least one of RF transmitter assemblies402, RF receiver assemblies 404, RF transceivers 406, magnetic resonancedetectors 408, gradient coil assemblies 410, RF coil assemblies 412,contrast agent detection assemblies 414, or the like. For example, in anembodiment, the means for affecting an in vivo magnetic resonancerelaxation process can include an RF transmitter assembly 402 includingone or more of controllers, digital attenuators, digital-to-analogconverters, amplifiers (e.g., power amplifiers, RF amplifiers, or thelike), RF synthesizer, signal conditioning amplifiers, transmittingcoils (e.g., RF transmitting coils, or the like), or waveformgenerators. In an embodiment, the means for affecting an in vivomagnetic resonance relaxation process can include at least one coilconfigured to generate one or more RF pulses based on, for example, acontrol input, output, a command, or a response an RF transmitteroperating in conjunction with, for example, but not limited to, an RFoscillator, generates an RF signal. This RF signal can be amplified bythe RF amplifier to, for example, drive and RF transmitter coil thatprovides RF pulses that excite the nuclear magnetization of non-zerospin nuclei of in a region of interest.

In an embodiment, the means for affecting an in vivo magnetic resonancerelaxation process can include circuitry for generating a response basedon the acquiring information.

In an embodiment, the response includes generating a representation(e.g., depiction, rendering, modeling, or the like) of at least onephysical parameter associated with one or more non-zero spin nuclei. Inan embodiment, the response includes generating a visual representationof at least one physical parameter associated with one or more non-zerospin nuclei. In an embodiment, the response includes generating a visualrepresentation of at least one physical characteristic associated withone or more non-zero spin nuclei. In an embodiment, the responseincludes a visual representation of at least one spectral parameterassociated with one or more non-zero spin nuclei. In an embodiment, theresponse includes generating a visual representation of at least onespectral parameter associated with one or more targeting moieties. In anembodiment, the response includes generating a visual representation ofat least one spectral parameter associated with one or moreferromagnetic microstructures. In an embodiment, the response includesgenerating a visual representation of at least one of ferromagneticmicrostructure spectral information, tissue-contained non-zero spinnuclei spectral information, tissue spectral information, indwellingimplant spectral information, fat spectral information, muscle spectralinformation, or bone spectral information.

In an embodiment, the response includes al least one of a visualrepresentation (e.g., a visual depiction representative of magneticallyactive object (e.g., a molecule, tissue, a ferromagnetic microstructure,or the like), a visual depiction representative of the detected (e.g.,assessed, calculated, evaluated, determined, gauged, measured,monitored, quantified, resolved, sensed, or the like) information), anaudio representation (e.g., an alarm, an audio waveform representationof a magnetic resonance event, or the like), or a tactile representation(e.g., a tactile diagram, a tactile display, a tactile graph, a tactileinteractive depiction, a tactile model (e.g., a multidimensional modelof a physical object or a magnetic resonance event, or the like), atactile pattern (e.g., a refreshable Braille display), a tactile-audiodisplay, a tactile-audio graph, or the like). In an embodiment, theresponse includes al least one of a display, a visual display, a visualdisplay of at least one spectral parameter, and the like. In anembodiment, the response includes an output, a response signal, adisplay, a data array, or a spectral plot. In an embodiment, theresponse includes one or more images associated with at least one of aspatial distribution of T₁ relaxation time information or a spatialdistribution of T₂ relaxation time information. In an embodiment, theresponse includes a visual representation indicative of a parameterassociated with one or more ferromagnetic microstructures. In anembodiment, the response includes automatically modifying at least oneof an RF power level, an RF pulsing protocol, or an RF detectionprotocol. In an embodiment, the response includes automaticallyaccumulating increments of detected RF information acquired over two ormore time intervals. In an embodiment, the response includesautomatically storing data indicative of detected RF information.

In an embodiment, the means for affecting an in vivo magnetic resonancerelaxation process can include circuitry for communicating the responseto a user. In an embodiment, the system 400 includes circuitry forgenerating an RF magnetic field of a character and for a sufficient timeto excite one or more of the nuclear magnetic resonance detectablenuclei received in the one or more voids 106 of the plurality offerromagnetic microstructures 102.

In an embodiment, the means for acquiring at least one spatialdistribution parameter of a magnetic resonance event associated with theaffected in vivo magnetic resonance relaxation process includes an RFreceiver assembly 402 configured to acquire RF information emitted bythe biological sample. In an embodiment, the means for affecting an invivo magnetic resonance relaxation process can include an RF transmitter404 configured to generate an RF signal. In an embodiment, the means foraffecting an in vivo magnetic resonance relaxation process includes oneor more coil assemblies 412 configured to generate one or more RFpulses.

In an embodiment, the means for acquiring at least one spatialdistribution parameter of a magnetic resonance event associated with theaffected in vivo magnetic resonance relaxation process includes one ormore controllers such as a processor (e.g., a microprocessor), a centralprocessing unit (CPU), a digital signal processor (DSP), anapplication-specific integrated circuit (ASIC), a field programmablegate array (FPGA), or the like, and any combinations thereof, and caninclude discrete digital or analog circuit elements or electronics, orcombinations thereof. The system 400 can include, but is not limited to,one or more field programmable gate arrays having a plurality ofprogrammable logic components. In an embodiment, the means for acquiringat least one spatial distribution parameter of a magnetic resonanceevent associated with the affected in vivo magnetic resonance relaxationprocess can include, but is not limited to, one or more applicationspecific integrated circuits having a plurality of predefined logiccomponents. The system 400 can include, but is not limited to, one ormore memories that, for example, store instructions or data, forexample, volatile memory (e.g., Random Access Memory (RAM), DynamicRandom Access Memory (DRAM), or the like), non-volatile memory (e.g.,Read-Only Memory (ROM), Electrically Erasable Programmable Read-OnlyMemory (EEPROM), Compact Disc Read-Only Memory (CD-ROM), or the like),persistent memory, or the like. Further examples of one or more memoriesinclude Erasable Programmable Read-Only Memory (EPROM), flash memory,and the like. The one or more memories can be coupled to, for example,one or more controllers by one or more instruction, data, or powerbuses.

In an embodiment, the means for acquiring at least one spatialdistribution parameter of a magnetic resonance event associated with theaffected in vivo magnetic resonance relaxation process can include, butis not limited to, data structures (e.g., physical data). In anembodiment, a data structure includes nuclear magnetic informationincluding one or more heuristically determined parameters associatedwith at least one in vivo or in vitro determined metric. Examples ofheuristics include, a heuristic protocol, heuristic algorithm, thresholdinformation, a target Larmor frequency, a target parameter, nuclearmagnetic resonance information, magnetic resonance spectral information,or the like. The system 400 can include, but is not limited to, a meansfor generating one or more heuristically determined parametersassociated with at least one in vivo or in vitro determined metricincluding one or more data structures. The system 400 can include, butis not limited to, a means for generating a response based on acomparison of detected nuclear magnetic information (e.g., an RF signal,a nuclear magnetic resonance, an in vivo magnetic resonance eventgenerated by nuclear magnetic resonance detectable nuclei, or the like)to one or more heuristically determined parameters stored in one or morephysical data structures, and to generate a response based on thecomparison.

In an embodiment, at least one of the one or more RF transmitterassemblies 402, RF receiver assemblies 404, RF transceivers 406,magnetic resonance detectors 408, gradient coil assemblies 410, orcontrast agent detection assemblies 414 can be, for example, wirelesslycoupled to a controller that communicates with a control unit of thesystem 400 via wireless communication. Examples of wirelesscommunication include for example, but not limited to, opticalconnections, ultraviolet connections, infrared, BLUETOOTH®, Internetconnections, radio, network connections, and the like. The system 100can include, but is not limited to, means for generating a responsebased on a comparison, of a detected at least one of an emittedinterrogation energy or a remitted interrogation energy to at least oneheuristically determined parameter, including one or more controllers.

In an embodiment, the system 400 includes means for generating aresponse based on an acquired at least one spatial distributionparameter. In an embodiment, magnetic resonance information generatedfrom an non-zero spin nuclei within an interrogation region are detectedby, one or more RF receiving coils and processed by the RF receiverassembly, including, for example, but not limited to, RF amplifiers,quadrature demodulator, and analog-to-digital converters.

In embodiment, a nuclear magnetic resonance imaging system includes aplurality of ferromagnetic microstructures 102. In an embodiment, one ormore of the plurality of ferromagnetic microstructures 102 include afirst internal surface 104 defining one or more voids 106, at least oneof the one or more voids 106 is configured to be accessible to abiological sample. In an embodiment, one or more of the plurality offerromagnetic microstructures 102 include a sufficient amount of one ormore ferromagnetic materials to generate a time-invariant magnetic field108 within at least a portion of at least one of the one or more voids106.

An aspect includes systems and devices including, among other things,means for affecting an in vivo magnetic resonance relaxation processassociated with a biological sample, in the absence of an externallygenerated magnetic field. A non-limiting approach includes means foracquiring at least one spatial distribution parameter of a magneticresonance event associated with the affected in vivo magnetic resonancerelaxation process, and means for generating a response based on anacquired at least one spatial distribution parameter. An aspect includessystems and devices including, among other things, circuitry foracquiring information associated with an in vivo magnetic resonanceevent generated by water molecule protons received in one or more voids106 of a plurality of ferromagnetic microstructures configured togenerate a static magnetic field within the void 106. An aspect includessystems and devices including, among other things, circuitry forgenerating a response based on acquiring information associated with anin vivo magnetic resonance event generated by water molecule protonsreceived in one or more voids 106 of a plurality of ferromagneticmicrostructures configured to generate a static magnetic field withinthe void 106. An aspect includes systems and devices including, amongother things, circuitry for communicating the response to a user. Anaspect includes systems and devices including, among other things,circuitry for generating an RF magnetic field of a character and for asufficient time to excite at least some of the water molecule protonsreceived in the one or more voids 106 of the plurality of ferromagneticmicrostructures.

An aspect includes systems, devices, methods, and compositions fordetecting regional information associated with a magnetic resonanceevent generated by in vivo target tissue-contained non-zero spin nucleiexposed to one or more voids 106 of a plurality of ferromagneticmicrostructures configured to generate a static magnetic flux densitywithin the void 106. A non-limiting approach includes systems, devices,methods, and compositions for affecting at least one of a protontransverse magnetic relaxation time or a proton longitudinal magneticrelaxation time associated with a biological sample by providing aplurality of ferromagnetic microstructures to at least a portion of thebiological sample, at least some of the plurality of ferromagneticmicrostructures including a first internal surface defining a void 106,the void 106 being selectively accessible to the biological sample, theplurality of ferromagnetic microstructures including a sufficient amountof at least one ferromagnetic material to generate a time-invariantmagnetic field within the void 106, the time-invariant magnetic field ofa sufficient character to affect at least one of a proton transversemagnetic relaxation time or a proton longitudinal magnetic relaxationtime associated with the biological sample.

FIGS. 5A and 5 b show an example of a method 500 for obtaining anon-external-magnet magnetic resonance image of a region within abiological subject. At 510, the method 500 includes detecting a spatialdistribution of a magnetic resonance event associated with a targetedbiological sample exposed to a surface-defined void 106 of aferromagnetic microstructure, the ferromagnetic microstructure 102configured to generate a static magnetic field within thesurface-defined void 106 and configured to affect a magnetic resonancerelaxation process associated with the biological sample at least whilethe biological sample is received in the surface-defined void 106. At512, detecting the spatial distribution of a magnetic resonance eventcan include detecting the spatial distribution of the magnetic resonanceevent associated with tissue-contained nuclear magnetic resonancedetectable nuclei exposed to the surface-defined void 106 of theferromagnetic microstructure. At 514, detecting the spatial distributionof a magnetic resonance event can include acquiring RF informationemitted by the tissue-contained nuclear magnetic resonance detectablenuclei exposed to the surface-defined void 106 of the ferromagneticmicrostructure 102. At 516, detecting the spatial distribution of amagnetic resonance event can include monitoring changes to at least oneof a T₁ magnetic relaxation time or a T₂ magnetic relaxation timeassociated with the tissue-contained nuclear magnetic resonancedetectable nuclei exposed to the surface-defined void 106 of theferromagnetic microstructure 102. At 518, detecting the spatialdistribution of a magnetic resonance event can include acquiring RFinformation associated with regional changes in the magnetic resonanceevent generated by the tissue-contained nuclear magnetic resonancedetectable nuclei exposed to the surface-defined void 106 of theferromagnetic microstructure 102. At 520, detecting the spatialdistribution of a magnetic resonance event can include detecting thespatial distribution of the magnetic resonance event associated withtissue-contained water protons exposed to the surface-defined void 106of the ferromagnetic microstructure 102. At 522, detecting the spatialdistribution of a magnetic resonance event can include acquiring RFinformation emitted by the tissue-contained water protons exposed to thesurface-defined void 106 of the ferromagnetic microstructure. At 524,detecting the spatial distribution of a magnetic resonance event caninclude monitoring changes to at least one of a T₁ magnetic relaxationtime or a T₂ magnetic relaxation time associated with thetissue-contained water protons exposed to the surface-defined void 106of the ferromagnetic microstructure. At 526, detecting the spatialdistribution of a magnetic resonance event can include acquiring RFinformation associated with regional changes in the magnetic resonanceevent generated by the tissue-contained water protons exposed to thesurface-defined void 106 of the ferromagnetic microstructure. At 528,detecting the spatial distribution of a magnetic resonance event caninclude detecting the spatial distribution of the magnetic resonanceevent associated with one or more NMR active nuclei. At 530, detectingthe spatial distribution of a magnetic resonance event can includedetecting the spatial distribution of the magnetic resonance eventassociated with one or more target spin species. At 532, detecting thespatial distribution of a magnetic resonance event can include detectingthe spatial distribution of the magnetic resonance event associated withone or more nuclei spins within an investigation region.

In an embodiment, detecting the spatial distribution of a magneticresonance event associated with the targeted biological sample exposedto the surface-defined void 106 of the ferromagnetic microstructure 102can include detecting the spatial distribution of a magnetic resonanceevent associated with the targeted biological sample exposed to thesurface-defined void of selectively-targeted ferromagneticmicrostructure. In an embodiment, detecting the spatial distribution ofa magnetic resonance event associated with the targeted biologicalsample exposed to the surface-defined void 106 of the ferromagneticmicrostructure 102 can include detecting the spatial distribution of amagnetic resonance event associated with the targeted biological sampleexposed to a selectively-accessible surface-defined void of theferromagnetic microstructure.

At 540, the method 500 includes generating a response based on thedetected spatial distribution of the magnetic resonance event. At 542,generating the response can include automatically modifying at least oneof an RF power level, an RF pulsing protocol, or an RF detectionprotocol. At 544, generating the response can include automaticallyaccumulating increments of detected RF information acquired over two ormore time intervals. At 546, generating the response can includeautomatically storing data indicative of detected RF information. In anembodiment, generating the response includes generating al least one ofa display, a visual representation (e.g., a plot, a display, a spectrum,a visual depiction representative of the detected information, a visualdepiction representative of a physical object (e.g., a ferromagneticmicrostructure, a contrast agent, tissue, an indwelling implant, fat,muscle, bone, non-zero spin nuclei, a biological fluid component, or thelike) a visual display, a visual display of at least one spectralparameter, and the like. In an embodiment, generating the responseincludes generating al least one of a visual representation, an audiorepresentation (e.g., an alarm, an audio waveform representation of amagnetic resonance event, or the like), or a tactile representation(e.g., a tactile diagram, a tactile display, a tactile graph, a tactileinteractive depiction, a tactile model (e.g., a multidimensional modelof a physical object or a magnetic resonance event, or the like), atactile pattern (e.g., a refreshable Braille display), a tactile-audiodisplay, a tactile-audio graph, or the like). In an embodiment,generating the response includes generating an output, a responsesignal, a display, a data array, or a spectral plot. In an embodiment,generating the response includes generating one or more imagesassociated with at least one of a spatial distribution of T₁ relaxationtime information or a spatial distribution of T₂ relaxation timeinformation. In an embodiment, generating the response includesgenerating at least one of a visual representation, an audiorepresentation, or a tactile representation indicative of a parameterassociated with one or more ferromagnetic microstructures. In anembodiment, generating the response includes generating at least one ofa visual representation, an audio representation, or a tactilerepresentation indicative of structure within a biological subject. Inan embodiment, generating the response includes generating at least oneof a visual representation, an audio representation, or a tactilerepresentation indicative of a physical condition within a biologicalsubject. In an embodiment, generating the response includes generatingat least one of a visual representation, an audio representation, or atactile representation indicative of a spatial distribution of pluralityof ferromagnetic microstructures 102 within a biological subject. In anembodiment, generating the response includes generating at least one ofa visual representation, an audio representation, or a tactilerepresentation indicative of at least one of a spatial distribution ofT₁ relaxation time information or a spatial distribution of T₂relaxation time information.

FIGS. 6A, 6B, and 6C show an example of a method 600 for obtaining amagnetic field resonance image. At 610, the method 600 includesdetecting a spatial distribution of a magnetic resonance eventassociated with one or more nuclear magnetic resonance detectable nucleiexposed to a plurality of target-selective microstructures. In anembodiment, at least a portion of the plurality of target-selectivemicrostructures include one or more surface-defined voids 106, and areconfigured to generate a static magnetic field within the one or moresurface-defined voids 106 and to affect a magnetic resonance relaxationprocess associated with the nuclear magnetic resonance detectable nucleiexposed to the generated static magnetic field. At 612, detecting thespatial distribution of the magnetic resonance event can includedetecting one or more magnetic relaxation parameters associated with theaffected magnetic resonance relaxation process associated with thenuclear magnetic resonance detectable nuclei interrogated by the staticmagnetic field. At 614, detecting the spatial distribution of themagnetic resonance event can include detecting a change to at least oneof a T₁ magnetic relaxation time or a T₂ magnetic relaxation timeassociated with the affected magnetic resonance relaxation processassociated with the nuclear magnetic resonance detectable nucleiinterrogated by the static magnetic field. At 616, detecting the spatialdistribution of the magnetic resonance event can include acquiring RFinformation associated with regional changes in the magnetic resonanceevent generated by the nuclear magnetic resonance detectable nucleiinterrogated by the static magnetic field. At 618, detecting the spatialdistribution of the magnetic resonance event can include inductivelyacquiring RF information associated with spatial differences in themagnetic resonance event generated by the nuclear magnetic resonancedetectable nuclei interrogated by the static magnetic field. At 620,detecting the spatial distribution of the magnetic resonance event caninclude detecting the spatial distribution of the magnetic resonanceevent associated with at least one of the one or more nuclear magneticresonance detectable nuclei exposed to a plurality of target-selectivemicrostructures having one or more targeting moieties 112 attached toone or more of the plurality of target-selective microstructures. At622, detecting the spatial distribution of the magnetic resonance eventincludes detecting the spatial distribution of the magnetic resonanceevent associated with spin ½ nuclei. At 624, detecting the spatialdistribution of the magnetic resonance event includes detecting thespatial distribution of the magnetic resonance event associated withtissue-contained spin ½ nuclei. At 626, detecting the spatialdistribution of the magnetic resonance includes detecting the spatialdistribution of the magnetic resonance event associated with hydrogennuclei. At 628, detecting the spatial distribution of the magneticresonance event includes detecting the spatial distribution of themagnetic resonance event associated with tissue-contained water protons.At 630, detecting the spatial distribution of the magnetic resonanceevent includes detecting one or more magnetic relaxation parametersassociated with the affected magnetic resonance relaxation processassociated with tissue-contained water protons interrogated by thestatic magnetic field. At 632, detecting the spatial distribution of themagnetic resonance event includes detecting the spatial distribution ofthe magnetic resonance event associated with one or more net nuclearspin isotopes. At 634, detecting the spatial distribution of themagnetic resonance event includes detecting the spatial distribution ofthe magnetic resonance event associated with tissue-contained waterprotons exposed to a plurality of ferromagnetic target-selectivemicrostructures. In an embodiment, detecting the spatial distribution ofthe magnetic resonance event can include detecting a spatialdistribution of a magnetic resonance event associated with one or morenuclear magnetic resonance detectable nuclei exposed to a plurality ofselectively-accessible, target-selective, microstructures. In anembodiment, at least a portion of the plurality of target-selectivemicrostructures include one or more components that selectively allownuclear magnetic resonance detectable nuclei to access the one or moresurface-defined voids. In an embodiment, detecting the spatialdistribution of the magnetic resonance event can include detecting aspatial distribution of a magnetic resonance event associated with oneor more nuclear magnetic resonance detectable nuclei exposed to aplurality of target-selective microstructures including one or moretargeting moieties attached thereof.

At 640, the method 600 includes providing a response based on thedetected spatial distribution of the magnetic resonance event. At 642,providing the response includes automatically providing informationassociated with least one of a transverse magnetic relaxation event or alongitudinal magnetic relaxation event associated with the detectedspatial distribution of the magnetic resonance event. At 644, providingthe response includes automatically providing information associatedwith at least one of a T₁ magnetic resonance process or a T₂ magneticresonance process. At 646, providing the response includes automaticallyproviding information associated with at least one of a water T₁magnetic resonance process or a water T₂ magnetic resonance process. At648, providing the response includes automatically providing at leastone of a tissue-contained water proton T₁ relaxation information, ortissue-contained water proton T₂ relaxation information. At 650,providing the response includes providing an image associated with atleast one of a spatial distribution of T₁ relaxation time information ora spatial distribution of T₂ relaxation time information. At 652,providing the response includes providing one or more T₁ maps. At 654,providing the response includes providing one or more T₂ maps. At 656,providing the response includes providing one or more T₁-weightedimages. See, e.g., U.S. Pat. No. 7,276,904 (issued Oct. 2, 2007) (thecontents of which are incorporated herein by reference). At 658,providing the response includes providing one or more T₂-weightedimages. At 660, providing the response includes providing acluster-based analysis of at least one of a quantitative T₁ relaxationmap, or a quantitative T₂ relaxation map. At 662, providing the responseincludes providing a voxel-based analysis of at least one of T₁relaxation information or a T₂ relaxation information. At 664, providingthe response includes providing a voxel-based analysis of at least oneof quantitative T₁ relaxation maps or quantitative T₂ relaxation maps.At 666, providing the response includes providing one or more magneticresonance images.

FIG. 7 shows an example of a multiplex imaging method 700. At 710, themethod 700 includes affecting at least one of a non-zero spin nucleitransverse magnetic relaxation time or a non-zero spin nucleilongitudinal magnetic relaxation time associated with a biologicalsample by providing a plurality of ferromagnetic microstructures to atleast a portion of the biological sample, at least some of the pluralityof ferromagnetic microstructures 102 including a first internal surfacedefining a void, the void being selectively accessible to the biologicalsample, the plurality of ferromagnetic microstructures including asufficient amount of at least one ferromagnetic material to generate atime-invariant magnetic field within the void, the time-invariantmagnetic field of a sufficient character to affect at least one of anon-zero spin nuclei transverse magnetic relaxation time or a non-zerospin nuclei longitudinal magnetic relaxation time associated with thebiological sample. In an embodiment, the plurality of ferromagneticmicrostructures 102 includes one or more ferromagnetic microstructuresets. In an embodiment, each ferromagnetic microstructure set includesone or more ferromagnetic microstructures 102 configured to include anaccessible internal void 106 and configured to generate a characteristictime-invariant magnetic field 108 within the accessible internal void106. In an embodiment, one or more of the ferromagnetic microstructuresets include a different characteristic time-invariant magnetic field108. At 720, the method 700 includes detecting at least one parameterassociated with the affected at least one of a non-zero spin nucleitransverse magnetic relaxation time or a non-zero spin nucleilongitudinal magnetic relaxation time associated with the biologicalsample. At 730, the method 700 includes generating a response based onthe detected at least one parameter.

FIG. 8 shows an example of a method 800 of multiplex interrogation of abiological sample. At 810, the method 800 includes detecting nuclearmagnetic resonance information generated by in vivo nuclear magneticresonance detectable nuclei exposed to one or moreinternal-surface-defined voids 106 of a plurality of differentferromagnetic microstructures configured to generate a static magneticflux density within at least a portion of the one or moreinternal-surface-defined voids 106 and configured to affect a magneticresonance relaxation process associated with the in vivo nuclearmagnetic resonance detectable nuclei while the in vivo nuclear magneticresonance detectable nuclei are received in at least one of the one ormore internal-surface-defined voids. At 812, detecting the nuclearmagnetic resonance information generated by in vivo nuclear magneticresonance detectable nuclei exposed to one or moreinternal-surface-defined voids 106 of a plurality of differentferromagnetic microstructures includes detecting nuclear magneticresonance information generated by in vivo nuclear magnetic resonancedetectable nuclei exposed to one or more internal-surface-defined voids106 of a plurality of different ferromagnetic microstructures having twoor more different characteristic time-invariant magnetic field 108. At814, detecting the nuclear magnetic resonance information generated byin vivo nuclear magnetic resonance detectable nuclei exposed to one ormore internal-surface-defined voids 106 of a plurality of differentferromagnetic microstructures includes detecting nuclear magneticresonance information generated by in vivo nuclear magnetic resonancedetectable nuclei exposed to one or more internal-surface-defined voids106 of a plurality of different ferromagnetic microstructures having twoor more different static magnetic flux densities. At 816, detecting thenuclear magnetic resonance information generated by in vivo nuclearmagnetic resonance detectable nuclei exposed to one or moreinternal-surface-defined voids 106 of a plurality of differentferromagnetic microstructures includes detecting nuclear magneticresonance information generated by in vivo nuclear magnetic resonancedetectable nuclei exposed to one or more internal-surface-defined voids106 of a plurality of different ferromagnetic microstructures linked toone or more different targeting moieties.

FIG. 9 shows an example of a method 900 for obtaining a non-externalmagnetic field resonance image of a region within a biological subject.At 910, the method 900 includes detecting a spatial distribution of amagnetic resonance event associated with one or more net nuclear spinisotopes exposed to a plurality of target-selective microstructuresconfigured to generate a static magnetic field within one or moresurface-defined voids 106 and to affect a magnetic resonance relaxationprocess associated with the net nuclear spin isotopes interrogated bythe generated static magnetic field. At 920, the method 900 may furtherinclude providing a response based on the detected spatial distributionof the magnetic resonance event. At 922, providing the response caninclude communicating the response to a user.

FIG. 10 shows an example of a method 1000. At 1010, the method 1000includes detecting a magnetic resonance event associated with one ormore nuclear magnetic resonance detectable nuclei exposed to a staticmagnetic field within one or more surface-defined voids 106 of aplurality of target-selective microstructures. At 1012, detectingmagnetic resonance event can include detecting a magnetic resonancerelaxation process associated with the nuclear magnetic resonancedetectable nuclei. At 1014, detecting the magnetic resonance event caninclude detecting a nuclear magnetic resonance event associated with atleast one of the plurality of different target-selective microstructureswithin the host. At 1016, detecting the magnetic resonance eventincludes detecting nuclear magnetic resonance signals from aninvestigation region resulting from a series of magnetic fieldgradients. At 1020, the method 1000 may further include administering toa host a composition comprising a plurality of differenttarget-selective microstructures, at least one of the plurality ofdifferent target-selective microstructures conjugated to one or moretargeting moieties.

FIG. 11 shows an example of a method 1100. At 1108, the method 1100includes detecting regional information associated with a magneticresonance event generated by in vivo target tissue-contained non-zerospin nuclei exposed to one or more voids 106 of a plurality offerromagnetic microstructures 102 configured to generate a staticmagnetic flux density within the void 106.

At 1110, detecting the regional information associated with the magneticresonance event includes detecting regional information associated witha magnetic resonance event generated by in vivo target tissue-containedspin ½ nuclei exposed to one or more voids 106 of a plurality offerromagnetic microstructures c configured to generate a static magneticflux density within the void 106.

At 1112, detecting the regional information associated with the magneticresonance event includes exposing target tissue-contained water protonsto the static magnetic flux density within the void 106 and detecting amagnetic relaxation associated with the target tissue-contained waterprotons. At 1114, detecting the regional information associated with themagnetic resonance event includes exposing the target tissue-containedspin ½ nuclei to the static magnetic flux density within the void 106and detecting a magnetic relaxation associated with the targettissue-contained spin ½ nuclei. At 1116, detecting the regionalinformation associated with the magnetic resonance event includesexposing the target tissue-contained spin ½ nuclei to the staticmagnetic flux density within the void 106 and detecting at least one ofa T₁ magnetic relaxation time or a T₂ magnetic relaxation timeassociated with the target tissue-contained spin ½ nuclei. At 1118,detecting the regional information associated with the magneticresonance event includes acquiring RF information associated with theregional information associated with the magnetic resonance eventgenerated by the target tissue-contained spin ½ nuclei. At 1120,detecting the regional information associated with the magneticresonance event includes acquiring one or more magnetic resonancesignals indicative of nuclear spins associated with the targettissue-contained spin ½ nuclei, via a plurality of RF coils. At 1122,detecting the regional information associated with the magneticresonance event includes acquiring one or more magnetic resonancesignals indicative of an in vivo T₁ relaxation parameter associated withthe target tissue-contained spin ½ nuclei. At 1124, detecting theregional information associated with the magnetic resonance eventincludes acquiring one or more magnetic resonance signals indicative ofan in vivo T₂ relaxation parameter associated with the targettissue-contained spin ½ nuclei. At 1130, the method 1100 includesgenerating a response based on the detected regional information.

FIG. 12 shows an example of a method 1200 for obtaining a magneticresonance image of a region within a biological subject in absence of anexternally generated magnetic field. At 1210, the method 1200 includesmonitoring a magnetic resonance event generated by net nuclear spinisotopes present in a biological sample received in a void 106 of aferromagnetic microstructure configured to generate a static magneticfield within the void 106. At 1212, monitoring the magnetic resonanceevent includes applying one or more RF pulses of a character and for asufficient time to excite one or more of the net nuclear spin isotopespresent in the biological sample and acquiring one or more magneticresonance signals associated with the magnetic resonance event generatedby net nuclear spin isotopes. At 1214, monitoring the magnetic resonanceevent includes acquiring magnetic relaxation information associated withregional changes in the magnetic resonance event generated by the netnuclear spin isotopes. At 1220, the method 1200 includes providing aresponse based on the monitored magnetic resonance event. At 1222,providing a response includes providing at least one of an output, aresponse signal, a display, a data array, or a spectral plot. At 1224,providing a response include providing one or more images associatedwith at least one of a spatial distribution of T₁ relaxation timeinformation or a spatial distribution of T₂ relaxation time information.

In an embodiment, a computer program product includes one or moresignal-bearing media containing computer instructions which, when run ona computing device, cause the computing device to implement a method1300. As shows in FIG. 13, at 1310, the method 1300 includes detecting aspatial distribution of a magnetic resonance event associated with abiological sample exposed to a surface-defined void 106 of aferromagnetic microstructure, the ferromagnetic microstructureconfigured to generate a static magnetic field within thesurface-defined void 106 and configured to affect a magnetic resonancerelaxation process associated with the biological sample at least whilethe biological sample is received in the surface-defined void 106. At1320, the method 1300 includes generating a response based on thedetected spatial distribution of the magnetic resonance event. At 1330,the method 1300 includes automatically communicating the response to auser.

FIG. 14 shows an example of a method 1400. At 1410, the method 1400includes affecting at least one of a non-zero spin nuclei transversemagnetic relaxation time or a non-zero spin nuclei longitudinal magneticrelaxation time associated with a biological sample by providing aplurality of ferromagnetic microstructures to at least a portion of thebiological sample, one or more of the plurality of ferromagneticmicrostructures including a first internal surface 104 defining a void106, the void 106 being selectively accessible to the biological sample,the plurality of ferromagnetic microstructures including a sufficientamount of at least one ferromagnetic material to generate atime-invariant magnetic field 108 within the void 106, thetime-invariant magnetic field 108 of a sufficient character to affect atleast one of a non-zero spin nuclei transverse magnetic relaxation timeor a non-zero spin nuclei longitudinal magnetic relaxation timeassociated with the biological sample of a sufficient character toaffect at least one of a non-zero spin nuclei transverse magneticrelaxation time or a non-zero spin nuclei longitudinal magneticrelaxation time associated with the biological sample of a sufficientcharacter to affect at least one of a non-zero spin nuclei transversemagnetic relaxation time or a non-zero spin nuclei longitudinal magneticrelaxation time associated with the biological sample of a sufficientcharacter to affect at least one of a non-zero spin nuclei transversemagnetic relaxation time or a non-zero spin nuclei longitudinal magneticrelaxation time associated with the biological sample. At 1420, themethod 1400 may further include detecting at least one parameterassociated with the affected at least one of a proton transversemagnetic relaxation time or a proton longitudinal magnetic relaxationtime associated with the biological sample. At 1430, the method 1400 mayfurther include generating a response based on the detected at least oneparameter.

FIGS. 15A through 15D show an example of a method 1500. At 1510, themethod 1500 includes detecting a spatial distribution of a magneticresonance event associated with a targeted biological sample exposed toa surface-defined void of one or more selectively-targeted ferromagneticmicrostructures, the one or more selectively-targeted ferromagneticmicrostructures configured to generate a static magnetic field withinthe surface-defined void and configured to affect a magnetic resonancerelaxation process associated with the biological sample at least whilethe biological sample is received in the surface-defined void. At 1512,detecting the spatial distribution of the magnetic resonance eventincludes detecting the spatial distribution of the magnetic resonanceevent associated with one or more ferromagnetic microstructuresselectively-targeted to at least one cell surface receptor targetingmoiety. At 1514, detecting the spatial distribution of the magneticresonance event includes detecting the spatial distribution of themagnetic resonance event associated with one or more ferromagneticmicrostructures selectively-targeted to include at least onetransmembrane receptor targeting moiety. At 1516, detecting the spatialdistribution of the magnetic resonance event includes detecting thespatial distribution of the magnetic resonance event associated with oneor more ferromagnetic microstructures selectively-targeted to at leastone antigen-targeting moiety. At 1518, detecting the spatialdistribution of the magnetic resonance event includes detecting thespatial distribution of the magnetic resonance event associated with oneor more ferromagnetic microstructures selectively-targeted to at leastone immune-receptor targeting moiety.

At 1520, detecting the spatial distribution of the magnetic resonanceevent includes detecting the spatial distribution of the magneticresonance event associated with one or more ferromagneticmicrostructures selectively-targeted to at least one folate receptortargeting moiety. At 1522, detecting the spatial distribution of themagnetic resonance event includes detecting the spatial distribution ofthe magnetic resonance event associated with one or more ferromagneticmicrostructures selectively-targeted to at least one nucleotide bindingmoiety. At 1524, detecting the spatial distribution of the magneticresonance event includes detecting the spatial distribution of themagnetic resonance event associated with one or more ferromagneticmicrostructures selectively-targeted to at least one oligonucleotidebinding moiety. At 1526, detecting the spatial distribution of themagnetic resonance event includes detecting the spatial distribution ofthe magnetic resonance event associated with one or more ferromagneticmicrostructures selectively-targeted to at least oneoligodeoxyribonucleotide binding moiety. At 1528, detecting the spatialdistribution of the magnetic resonance event includes detecting thespatial distribution of the magnetic resonance event associated with oneor more ferromagnetic microstructures selectively-targeted to at leastone oligoribonucleotide binding moiety.

At 1530, detecting the spatial distribution of the magnetic resonanceevent includes detecting the spatial distribution of the magneticresonance event associated with one or more ferromagneticmicrostructures selectively-targeted to at least one amyloid bindingmoiety. At 1532, detecting the spatial distribution of the magneticresonance event includes detecting the spatial distribution of themagnetic resonance event associated with one or more ferromagneticmicrostructures selectively-targeted to at least one β-amyloid bindingmoiety. At 1534, detecting the spatial distribution of the magneticresonance event includes detecting the spatial distribution of themagnetic resonance event associated with one or more ferromagneticmicrostructures selectively-targeted to one or more genomic targets. At1536, detecting the spatial distribution of the magnetic resonance eventincludes detecting the spatial distribution of the magnetic resonanceevent associated with one or more ferromagnetic microstructuresselectively-targeted to at least one oncogene. At 1538, detecting thespatial distribution of the magnetic resonance event includes detectingthe spatial distribution of the magnetic resonance event associated withone or more ferromagnetic microstructures selectively-targeted to atleast one chromosome translocation.

At 1540, detecting the spatial distribution of the magnetic resonanceevent includes detecting the spatial distribution of the magneticresonance event associated with one or more ferromagneticmicrostructures selectively-targeted to at least one methylateddeoxyribonucleic acid sequence. At 1542, detecting the spatialdistribution of the magnetic resonance event includes detecting thespatial distribution of the magnetic resonance event associated with oneor more ferromagnetic microstructures selectively-targeted to at leastone methylated deoxyribonucleic acid sequence including a methylatedcytosine. At 1544, detecting the spatial distribution of the magneticresonance event includes detecting the spatial distribution of themagnetic resonance event associated with one or more ferromagneticmicrostructures selectively-targeted to at least one methylatedribonucleic acid sequence. At 1546, detecting the spatial distributionof the magnetic resonance event includes detecting the spatialdistribution of the magnetic resonance event associated with one or moreferromagnetic microstructures selectively-targeted to at least onedeoxyribonucleic acid sequence including unmethylated cytosine.

At 1548, detecting the spatial distribution of the magnetic resonanceevent includes detecting the spatial distribution of the magneticresonance event associated with one or more ferromagneticmicrostructures selectively-targeted to at least one single-nucleotidepolymorphism. At 1550, detecting the spatial distribution of themagnetic resonance event includes detecting the spatial distribution ofthe magnetic resonance event associated with one or more ferromagneticmicrostructures selectively-targeted to at least one of a somaticmutation, germline mutation, chemically induced mutation, biologicallyinduce mutation, or an environmentally induce mutation. At 1552,detecting the spatial distribution of the magnetic resonance eventincludes detecting the spatial distribution of the magnetic resonanceevent associated with one or more ferromagnetic microstructuresselectively-targeted to at least one double stranded deoxyribonucleicacid sequence. At 1554, detecting the spatial distribution of themagnetic resonance event includes detecting the spatial distribution ofthe magnetic resonance event associated with one or more ferromagneticmicrostructures selectively-targeted to at least one single strandeddeoxyribonucleic acid sequence. At 1556, detecting the spatialdistribution of the magnetic resonance event includes detecting thespatial distribution of the magnetic resonance event associated with oneor more ferromagnetic microstructures selectively-targeted to at leastone mitochondrial deoxyribonucleic acid sequence. At 1558, detecting thespatial distribution of the magnetic resonance event includes detectingthe spatial distribution of the magnetic resonance event associated withone or more ferromagnetic microstructures selectively-targeted to atleast one of a point mutation, an insertion of one or more nucleotides,or a deletion of one or more nucleotides.

At 1560, detecting the spatial distribution of the magnetic resonanceevent includes detecting the spatial distribution of the magneticresonance event associated with one or more ferromagneticmicrostructures selectively-targeted to at least a portion of a humanchromosome in vivo. At 1562, detecting the spatial distribution of themagnetic resonance event includes detecting the spatial distribution ofthe magnetic resonance event associated with one or more ferromagneticmicrostructures selectively-targeted to a zinc finger-including protein.At 1564, detecting the spatial distribution of the magnetic resonanceevent includes detecting the spatial distribution of the magneticresonance event associated with one or more ferromagneticmicrostructures selectively-targeted to a deoxyribonucleic acidsequence. At 1566, detecting the spatial distribution of the magneticresonance event includes detecting the spatial distribution of themagnetic resonance event associated with one or more ferromagneticmicrostructures selectively-targeted to a ribonucleic acid sequencetarget. At 1568, detecting the spatial distribution of the magneticresonance event includes detecting the spatial distribution of themagnetic resonance event associated with one or more ferromagneticmicrostructures selectively-targeted to an antigen epitope. At 1570,detecting the spatial distribution of the magnetic resonance eventincludes detecting the spatial distribution of the magnetic resonanceevent associated with one or more ferromagnetic microstructuresselectively-targeted to an antigen mimotope. At 1572, detecting thespatial distribution of the magnetic resonance event includes detectinga spatial distribution of a magnetic resonance event associated with thetargeted biological sample exposed to a selectively-accessiblesurface-defined void of one or more selectively-targeted,selectively-accessible, ferromagnetic microstructures.

At 1580, the method 1500 includes generating a response based on thedetected spatial distribution of the magnetic resonance event.

FIG. 16 shows an example of a method 1600.

At 1610, the method 1600 includes affecting at least one of a non-zerospin nuclei transverse magnetic relaxation time or a non-zero spinnuclei longitudinal magnetic relaxation time associated with abiological sample by providing a plurality of target-specificferromagnetic microstructures to at least a portion of the biologicalsample, at least some of the target-specific ferromagneticmicrostructures including a first internal surface defining a void, thevoid being selectively accessible to the biological sample, thetarget-specific ferromagnetic microstructures including a sufficientamount of at least one ferromagnetic material to generate atime-invariant magnetic field within the void, the time-invariantmagnetic field of a sufficient character to affect at least one of anon-zero spin nuclei transverse magnetic relaxation time or a non-zerospin nuclei longitudinal magnetic relaxation time associated with thebiological sample. At 1612, affecting the at least one of a non-zerospin nuclei transverse magnetic relaxation time or the non-zero spinnuclei longitudinal magnetic relaxation time includes affecting at leastone of a proton transverse magnetic relaxation time or a protonlongitudinal magnetic relaxation time associated with a biologicalsample by providing a plurality of target-specific ferromagneticmicrostructures to at least a portion of the biological sample. At 1614,affecting the at least one of a non-zero spin nuclei transverse magneticrelaxation time or a non-zero spin nuclei longitudinal magneticrelaxation time includes providing a sufficient amount of a plurality oftarget-specific ferromagnetic microstructures including one or moretargeting moieties attached thereof to at least a portion of thebiological sample to affecting the at least one of a non-zero spinnuclei transverse magnetic relaxation time or a non-zero spin nucleilongitudinal magnetic relaxation time associated with a biologicalsample.

At 1620, the method 1600 includes detecting at least one parameterassociated with the affected at least one of a non-zero spin nucleitransverse magnetic relaxation time or a non-zero spin nucleilongitudinal magnetic relaxation time associated with the biologicalsample. At 1630, the method 1600 includes generating a response based onthe detected at least one parameter.

FIGS. 17A through 17R show an example of a method 1700.

At 1710, the method 1700 can include detecting a spatial distribution ofa magnetic resonance event associated with a targeted biological sampleexposed to a surface-defined void 106 of a ferromagnetic microstructure,the ferromagnetic microstructure configured to generate a staticmagnetic field within the surface-defined void 106 and configured toaffect a magnetic resonance relaxation process associated with thebiological sample at least while the biological sample is received inthe surface-defined void 106. At 1712, detecting the spatialdistribution of a magnetic resonance event can include detecting thespatial distribution of the magnetic resonance event associated withtissue-contained nuclear magnetic resonance detectable nuclei exposed tothe surface-defined void 106 of the ferromagnetic microstructure. At1714, detecting the spatial distribution of a magnetic resonance eventcan include acquiring RF information emitted by the tissue-containednuclear magnetic resonance detectable nuclei exposed to thesurface-defined void 106 of the ferromagnetic microstructure. At 1716,detecting the spatial distribution of a magnetic resonance event caninclude monitoring changes to at least one of a T₁ magnetic relaxationtime or a T₂ magnetic relaxation time associated with thetissue-contained nuclear magnetic resonance detectable nuclei exposed tothe surface-defined void 106 of the ferromagnetic microstructure. At1718, detecting the spatial distribution of a magnetic resonance eventcan include acquiring RF information associated with regional changes inthe magnetic resonance event generated by the tissue-contained nuclearmagnetic resonance detectable nuclei exposed to the surface-defined void106 of the ferromagnetic microstructure. At 1720, detecting the spatialdistribution of a magnetic resonance event can include detecting thespatial distribution of the magnetic resonance event associated withtissue-contained water protons exposed to the surface-defined void 106of the ferromagnetic microstructure. At 1722, detecting the spatialdistribution of a magnetic resonance event can include acquiring RFinformation emitted by the tissue-contained water protons exposed to thesurface-defined void 106 of the ferromagnetic microstructure. At 1724,detecting the spatial distribution of a magnetic resonance event caninclude monitoring changes to at least one of a T₁ magnetic relaxationtime or a T₂ magnetic relaxation time associated with thetissue-contained water protons exposed to the surface-defined void 106of the ferromagnetic microstructure. At 1726, detecting the spatialdistribution of a magnetic resonance event can include acquiring RFinformation associated with regional changes in the magnetic resonanceevent generated by the tissue-contained water protons exposed to thesurface-defined void 106 of the ferromagnetic microstructure. At 1728,detecting the spatial distribution of a magnetic resonance event caninclude detecting the spatial distribution of the magnetic resonanceevent associated with one or more NMR active nuclei. At 1730, detectingthe spatial distribution of a magnetic resonance event can includedetecting the spatial distribution of the magnetic resonance eventassociated with one or more target spin species. At 1732, detecting thespatial distribution of a magnetic resonance event can include detectingthe spatial distribution of the magnetic resonance event associated withone or more nuclei spins within an investigation region.

At 1734, the method 1700 can include generating a response based on thedetected spatial distribution of the magnetic resonance event.

At 1736, generating the response can include automatically modifying atleast one of an RF power level, an RF pulsing protocol, or an RFdetection protocol. At 1738, generating the response can includeautomatically accumulating increments of detected RF informationacquired over two or more time intervals. At 1740, generating theresponse can include automatically storing data indicative of detectedRF information.

At 1742, the method 1700 can include detecting a spatial distribution ofa magnetic resonance event associated with one or more nuclear magneticresonance detectable nuclei exposed to a plurality of target-selectivemicrostructures. In an embodiment, at least a portion of the pluralityof target-selective microstructures include one or more surface-definedvoids 106, and are configured to generate a static magnetic field withinthe one or more surface-defined voids 106 and to affect a magneticresonance relaxation process associated with the nuclear magneticresonance detectable nuclei exposed to the generated static magneticfield. At 1744, detecting the spatial distribution of the magneticresonance event can include detecting one or more magnetic relaxationparameters associated with the affected magnetic resonance relaxationprocess associated with the nuclear magnetic resonance detectable nucleiinterrogated by the static magnetic field. At 1746, detecting thespatial distribution of the magnetic resonance event can includedetecting a change to at least one of a T₁ magnetic relaxation time or aT₂ magnetic relaxation time associated with the affected magneticresonance relaxation process associated with the nuclear magneticresonance detectable nuclei interrogated by the static magnetic field.At 1748, detecting the spatial distribution of the magnetic resonanceevent can include acquiring RF information associated with regionalchanges in the magnetic resonance event generated by the nuclearmagnetic resonance detectable nuclei interrogated by the static magneticfield. At 1750, detecting the spatial distribution of the magneticresonance event can include inductively acquiring RF informationassociated with spatial differences in the magnetic resonance eventgenerated by the nuclear magnetic resonance detectable nucleiinterrogated by the static magnetic field. At 1752, detecting thespatial distribution of the magnetic resonance event can includedetecting the spatial distribution of the magnetic resonance eventassociated with at least one of the one or more nuclear magneticresonance detectable nuclei exposed to a plurality of target-selectivemicrostructures having one or more targeting moieties 112 attached toone or more of the plurality of target-selective microstructures.

At 1754, detecting the spatial distribution of the magnetic resonanceevent includes detecting the spatial distribution of the magneticresonance event associated with spin ½ nuclei. At 1756, detecting thespatial distribution of the magnetic resonance event includes detectingthe spatial distribution of the magnetic resonance event associated withtissue-contained spin ½ nuclei. At 1758, detecting the spatialdistribution of the magnetic resonance includes detecting the spatialdistribution of the magnetic resonance event associated with hydrogennuclei. At 1760, detecting the spatial distribution of the magneticresonance event includes detecting the spatial distribution of themagnetic resonance event associated with tissue-contained water protons.At 1762, detecting the spatial distribution of the magnetic resonanceevent includes detecting one or more magnetic relaxation parametersassociated with the affected magnetic resonance relaxation processassociated with tissue-contained water protons interrogated by thestatic magnetic field. At 1764, detecting the spatial distribution ofthe magnetic resonance event includes detecting the spatial distributionof the magnetic resonance event associated with one or more net nuclearspin isotopes. At 1766, detecting the spatial distribution of themagnetic resonance event includes detecting the spatial distribution ofthe magnetic resonance event associated with tissue-contained waterprotons exposed to a plurality of ferromagnetic target-selectivemicrostructures.

At 1768, the method 1700 can include providing a response based on thedetected spatial distribution of the magnetic resonance event. At 1770,providing the response includes automatically providing informationassociated with least one of a transverse magnetic relaxation event or alongitudinal magnetic relaxation event associated with the detectedspatial distribution of the magnetic resonance event. At 1772, providingthe response includes automatically providing information associatedwith at least one of a T₁ magnetic resonance process or a T₂ magneticresonance process. At 1774, providing the response includesautomatically providing information associated with at least one of awater T₁ magnetic resonance process or a water T₂ magnetic resonanceprocess. At 1776, providing the response includes automaticallyproviding at least one of a tissue-contained water proton T₁ relaxationinformation, or tissue-contained water proton T₂ relaxation information.At 1778, providing the response includes providing an image associatedwith at least one of a spatial distribution of T₁ relaxation timeinformation or a spatial distribution of T₂ relaxation time information.At 1780, providing the response includes providing one or more T₁ maps.At 1782, providing the response includes providing one or more T₂ maps.At 1784, providing the response includes providing one or moreT₁-weighted images. See, e.g., U.S. Pat. No. 7,276,904 (issued Oct. 2,2007) (the contents of which are incorporated herein by reference). At1786, providing the response includes providing one or more T₂-weightedimages. At 1788, providing the response includes providing acluster-based analysis of at least one of a quantitative T₁ relaxationmap, or a quantitative T₂ relaxation map. At 1790, providing theresponse includes providing a voxel-based analysis of at least one of T₁relaxation information or a T₂ relaxation information. At 1792,providing the response includes providing a voxel-based analysis of atleast one of quantitative T₁ relaxation maps or quantitative T₂relaxation maps. At 1793, providing the response includes providing oneor more magnetic resonance images.

At 1794, the method 1700 can include affecting at least one of anon-zero spin nuclei transverse magnetic relaxation time or a non-zerospin nuclei longitudinal magnetic relaxation time associated with abiological sample by providing a plurality of ferromagneticmicrostructures to at least a portion of the biological sample, at leastsome of the plurality of ferromagnetic microstructures including a firstinternal surface defining a void, the void being selectively accessibleto the biological sample, the plurality of ferromagnetic microstructuresincluding a sufficient amount of at least one ferromagnetic material togenerate a time-invariant magnetic field within the void, thetime-invariant magnetic field of a sufficient character to affect atleast one of a non-zero spin nuclei transverse magnetic relaxation timeor a non-zero spin nuclei longitudinal magnetic relaxation timeassociated with the biological sample. At 1795, affecting at least oneof a non-zero spin nuclei transverse magnetic relaxation time or anon-zero spin nuclei longitudinal magnetic relaxation time can includeaffecting at least one of a proton transverse magnetic relaxation timeor a proton longitudinal magnetic relaxation time associated with abiological sample by providing a plurality of ferromagneticmicrostructures to at least a portion of the biological sample.

At 1796, the method 1700 can include detecting at least one parameterassociated with the affected at least one of a non-zero spin nucleitransverse magnetic relaxation time or a non-zero spin nucleilongitudinal magnetic relaxation time associated with the biological,sample.

At 1798, the method 1700 can include generating a response based on thedetected at least one parameter.

At 1800, the method 1700 can include detecting nuclear magneticresonance information generated by in vivo nuclear magnetic resonancedetectable nuclei exposed to one or more internal-surface-defined voids106 of a plurality of different ferromagnetic microstructures configuredto generate a static magnetic flux density within at least a portion ofthe one or more internal-surface-defined voids 106 and configured toaffect a magnetic resonance relaxation process associated with the invivo nuclear magnetic resonance detectable nuclei while the in vivonuclear magnetic resonance detectable nuclei are received in at leastone of the one or more internal-surface-defined voids. At 1802,detecting the nuclear magnetic resonance information includes detectingnuclear magnetic resonance information generated by in vivo nuclearmagnetic resonance detectable nuclei exposed to one or moreinternal-surface-defined voids 106 of a plurality of differentferromagnetic microstructures having two or more differentcharacteristic time-invariant magnetic field 108. At 1804, detecting thenuclear magnetic resonance information includes detecting nuclearmagnetic resonance information generated by in vivo nuclear magneticresonance detectable nuclei exposed to one or moreinternal-surface-defined voids 106 of a plurality of differentferromagnetic microstructures having two or more different staticmagnetic flux densities. At 1806, detecting the nuclear magneticresonance information includes detecting nuclear magnetic resonanceinformation generated by in vivo nuclear magnetic resonance detectablenuclei exposed to one or more internal-surface-defined voids 106 of aplurality of different ferromagnetic microstructures linked to one ormore different targeting moieties. At 1808, the method 1700 can includedetecting a spatial distribution of a magnetic resonance eventassociated with one or more net nuclear spin isotopes exposed to aplurality of target-selective microstructures configured to generate astatic magnetic field within one or more surface-defined voids 106 andto affect a magnetic resonance relaxation process associated with thenet nuclear spin isotopes interrogated by the generated static magneticfield.

At 1810, the method 1700 can include providing a response based on thedetected spatial distribution of the magnetic resonance event. At 1812,providing the response can include communicating the response to a user.

At 1814, the method 1700 can include detecting a magnetic resonanceevent associated with one or more nuclear magnetic resonance detectablenuclei exposed to a static magnetic field within one or moresurface-defined voids 106 of a plurality of target-selectivemicrostructures. At 1816, detecting magnetic resonance event can includedetecting a magnetic resonance relaxation process associated with thenuclear magnetic resonance detectable nuclei. At 1818, detecting themagnetic resonance event can include detecting a nuclear magneticresonance event associated with at least one of the plurality ofdifferent target-selective microstructures within the host. At 1820,detecting the magnetic resonance event includes detecting nuclearmagnetic resonance signals from an investigation region resulting from aseries of magnetic field gradients. At 1822, the method 1700 can includeadministering to a host a composition comprising a plurality ofdifferent target-selective microstructures, at least one of theplurality of different target-selective microstructures conjugated toone or more targeting moieties.

At 1824, the method 1700 can include detecting regional informationassociated with a magnetic resonance event generated by in vivo targettissue-contained non-zero spin nuclei exposed to one or more voids 106of a plurality of ferromagnetic microstructures 102 configured togenerate a static magnetic flux density within the void 106. At 1826,detecting the regional information associated with the magneticresonance event includes detecting regional information associated witha magnetic resonance event generated by in vivo target tissue-containedspin ½ nuclei exposed to one or more voids 106 of a plurality offerromagnetic microstructures 102 configured to generate a staticmagnetic flux density within the void 106. At 1828, detecting theregional information associated with the magnetic resonance eventincludes exposing target tissue-contained water protons to the staticmagnetic flux density within the void 106 and detecting a magneticrelaxation associated with the target tissue-contained water protons. At1830, detecting the regional information associated with the magneticresonance event includes exposing the target tissue-contained spin ½nuclei to the static magnetic flux density within the void 106 anddetecting a magnetic relaxation associated with the targettissue-contained spin ½ nuclei. At 1832, detecting the regionalinformation associated with the magnetic resonance event includesexposing the target tissue-contained spin ½ nuclei to the staticmagnetic flux density within the void 106 and detecting at least one ofa T₁ magnetic relaxation time or a T₂ magnetic relaxation timeassociated with the target tissue-contained spin ½ nuclei. At 1834,detecting the regional information associated with the magneticresonance event includes acquiring RF information associated with theregional information associated with the magnetic resonance eventgenerated by the target tissue-contained spin ½ nuclei. At 1836,detecting the regional information associated with the magneticresonance event includes acquiring one or more magnetic resonancesignals indicative of nuclear spins associated with the targettissue-contained spin ½ nuclei, via a plurality of RF coils. At 1838,detecting the regional information associated with the magneticresonance event includes acquiring one or more magnetic resonancesignals indicative of an in vivo T₁ relaxation parameter associated withthe target tissue-contained spin ½ nuclei. At 1840, detecting theregional information associated with the magnetic resonance eventincludes acquiring one or more magnetic resonance signals indicative ofan in vivo T₂ relaxation parameter associated with the targettissue-contained spin ½ nuclei. At 1842, the method 1700 can includegenerating a response based on the detected regional information.

At 1844, the method 1700 can include monitoring a magnetic resonanceevent generated by net nuclear spin isotopes present in a biologicalsample received in a void 106 of a ferromagnetic microstructureconfigured to generate a static magnetic field within the void 106. At1846, monitoring the magnetic resonance event includes applying one ormore RF pulses of a character and for a sufficient time to excite one ormore of the net nuclear spin isotopes present in the biological sampleand acquiring one or more magnetic resonance signals associated with themagnetic resonance event generated by net nuclear spin isotopes. At1848, monitoring the magnetic resonance event includes acquiringmagnetic relaxation information associated with regional changes in themagnetic resonance event generated by the net nuclear spin isotopes.

At 1850, the method 1700 can include providing a response based on themonitored magnetic resonance event. At 1852, providing a responseincludes providing at least one of an output, a response signal, adisplay, a data array, or a spectral plot. At 1854, providing a responseinclude providing one or more images associated with at least one of aspatial distribution of T₁ relaxation time information or a spatialdistribution of T₂ relaxation time information.

At 1856, the method 1700 can include detecting a spatial distribution ofa magnetic resonance event associated with a biological sample exposedto a surface-defined void 106 of a ferromagnetic microstructure, theferromagnetic microstructure configured to generate a static magneticfield within the surface-defined void 106 and configured to affect amagnetic resonance relaxation process associated with the biologicalsample at least while the biological sample is received in thesurface-defined void 106.

At 1858, the method 1700 includes generating a response based on thedetected spatial distribution of the magnetic resonance event.

At 1860, the method 1700 includes automatically communicating theresponse to a user.

At 1862, the method 1700 can include affecting at least one of a protontransverse magnetic relaxation time or a proton longitudinal magneticrelaxation time associated with a biological sample by providing aplurality of ferromagnetic microstructures to at least a portion of thebiological sample, one or more of the plurality of ferromagneticmicrostructures including a first internal surface 104 defining a void106, the void 106 being selectively accessible to the biological sample,the plurality of ferromagnetic microstructures including a sufficientamount of at least one ferromagnetic material to generate atime-invariant magnetic field 108 within the void 106, thetime-invariant magnetic field 108 of a sufficient character to affect atleast one of a proton transverse magnetic relaxation time or a protonlongitudinal magnetic relaxation time associated with the biologicalsample.

At 1864, the method 1700 can include detecting at least one parameterassociated with the affected at least one of a proton transversemagnetic relaxation time or a proton longitudinal magnetic relaxationtime associated with the biological sample.

At 1866, the method 1700 can include generating a response based on thedetected at least one parameter.

At 1868, the method 1700 can include detecting a spatial distribution ofa magnetic resonance event associated with a targeted biological sampleexposed to a surface-defined void of one or more selectively-targetedferromagnetic microstructures, the one or more selectively-targetedferromagnetic microstructures configured to generate a static magneticfield within the surface-defined void and configured to affect amagnetic resonance relaxation process associated with the biologicalsample at least while the biological sample is received in thesurface-defined void. At 1870, detecting the spatial distribution of themagnetic resonance event includes detecting the spatial distribution ofthe magnetic resonance event associated with one or more ferromagneticmicrostructures selectively-targeted to at least one cell surfacereceptor targeting moiety. At 1872, detecting the spatial distributionof the magnetic resonance event includes detecting the spatialdistribution of the magnetic resonance event associated with one or moreferromagnetic microstructures selectively-targeted to include at leastone transmembrane receptor targeting moiety. At 1874, detecting thespatial distribution of the magnetic resonance event includes detectingthe spatial distribution of the magnetic resonance event associated withone or more ferromagnetic microstructures selectively-targeted to atleast one antigen-targeting moiety. At 1876, detecting the spatialdistribution of the magnetic resonance event includes detecting thespatial distribution of the magnetic resonance event associated with oneor more ferromagnetic microstructures selectively-targeted to at leastone immune-receptor targeting moiety. At 1878, detecting the spatialdistribution of the magnetic resonance event includes detecting thespatial distribution of the magnetic resonance event associated with oneor more ferromagnetic microstructures selectively-targeted to at leastone folate receptor targeting moiety. At 1880, detecting the spatialdistribution of the magnetic resonance event includes detecting thespatial distribution of the magnetic resonance event associated with oneor more ferromagnetic microstructures selectively-targeted to at leastone nucleotide binding moiety. At 1882, detecting the spatialdistribution of the magnetic resonance event includes detecting thespatial distribution of the magnetic resonance event associated with oneor more ferromagnetic microstructures selectively-targeted to at leastone oligonucleotide binding moiety. At 1884, detecting the spatialdistribution of the magnetic resonance event includes detecting thespatial distribution of the magnetic resonance event associated with oneor more ferromagnetic microstructures selectively-targeted to at leastone oligodeoxyribonucleotide binding moiety. At 1886, detecting thespatial distribution of the magnetic resonance event includes detectingthe spatial distribution of the magnetic resonance event associated withone or more ferromagnetic microstructures selectively-targeted to atleast one oligoribonucleotide binding moiety. At 1888, detecting thespatial distribution of the magnetic resonance event includes detectingthe spatial distribution of the magnetic resonance event associated withone or more ferromagnetic microstructures selectively-targeted to atleast one amyloid binding moiety. At 1890, detecting the spatialdistribution of the magnetic resonance event includes detecting thespatial distribution of the magnetic resonance event associated with oneor more ferromagnetic microstructures selectively-targeted to at leastone β-amyloid binding moiety. At 1892, detecting the spatialdistribution of the magnetic resonance event associated includesdetecting the spatial distribution of the magnetic resonance eventassociated with one or more ferromagnetic microstructuresselectively-targeted to one or more genomic targets. At 1894, detectingthe spatial distribution of the magnetic resonance event includesdetecting the spatial distribution of the magnetic resonance eventassociated with one or more ferromagnetic microstructuresselectively-targeted to at least one oncogene. At 1896, detecting thespatial distribution of the magnetic resonance event includes detectingthe spatial distribution of the magnetic resonance event associated withone or more ferromagnetic microstructures selectively-targeted to atleast one chromosome translocation. At 1898, detecting the spatialdistribution of the magnetic resonance event includes detecting thespatial distribution of the magnetic resonance event associated with oneor more ferromagnetic microstructures selectively-targeted to at leastone methylated deoxyribonucleic acid sequence. At 1900, detecting thespatial distribution of the magnetic resonance event includes detectingthe spatial distribution of the magnetic resonance event associated withone or more ferromagnetic microstructures selectively-targeted to atleast one methylated deoxyribonucleic acid sequence including amethylated cytosine. At 1902, detecting the spatial distribution of themagnetic resonance event includes detecting the spatial distribution ofthe magnetic resonance event associated with one or more ferromagneticmicrostructures selectively-targeted to at least one methylatedribonucleic acid sequence. At 1904, detecting the spatial distributionof the magnetic resonance event includes detecting the spatialdistribution of the magnetic resonance event associated with one or moreferromagnetic microstructures selectively-targeted to at least onedeoxyribonucleic acid sequence including unmethylated cytosine. At 1906,detecting the spatial distribution of the magnetic resonance eventincludes detecting the spatial distribution of the magnetic resonanceevent associated with one or more ferromagnetic microstructuresselectively-targeted to at least one single-nucleotide polymorphism. At1908, detecting the spatial distribution of the magnetic resonance eventincludes detecting the spatial distribution of the magnetic resonanceevent associated with one or more ferromagnetic microstructuresselectively-targeted to at least one of a somatic mutation, germlinemutation, chemically induced mutation, biologically induce mutation, oran environmentally induce mutation. At 1910, detecting the spatialdistribution of the magnetic resonance event includes detecting thespatial distribution of the magnetic resonance event associated with oneor more ferromagnetic microstructures selectively-targeted to at leastone double stranded deoxyribonucleic acid sequence. At 1912, detectingthe spatial distribution of the magnetic resonance event includesdetecting the spatial distribution of the magnetic resonance eventassociated with one or more ferromagnetic microstructuresselectively-targeted to at least one single stranded deoxyribonucleicacid sequence. At 1914, detecting the spatial distribution of themagnetic resonance event includes detecting the spatial distribution ofthe magnetic resonance event associated with one or more ferromagneticmicrostructures selectively-targeted to at least one mitochondrialdeoxyribonucleic acid sequence At 1916, detecting the spatialdistribution of the magnetic resonance event includes detecting thespatial distribution of the magnetic resonance event associated with oneor more ferromagnetic microstructures selectively-targeted to at leastone of a point mutation, an insertion of one or more nucleotides, or adeletion of one or more nucleotides. At 1918, detecting the spatialdistribution of the magnetic resonance event includes detecting thespatial distribution of the magnetic resonance event associated with oneor more ferromagnetic microstructures selectively-targeted to at least aportion of a human chromosome in vivo. At 1920, detecting the spatialdistribution of the magnetic resonance event includes detecting thespatial distribution of the magnetic resonance event associated with oneor more ferromagnetic microstructures selectively-targeted to a zincfinger-including protein. At 1922, detecting the spatial distribution ofthe magnetic resonance event includes detecting the spatial distributionof the magnetic resonance event associated with one or moreferromagnetic microstructures selectively-targeted to a deoxyribonucleicacid sequence. At 1924, detecting the spatial distribution of themagnetic resonance event includes detecting the spatial distribution ofthe magnetic resonance event associated with one or more ferromagneticmicrostructures selectively-targeted to a ribonucleic acid sequencetarget. At 1926, detecting the spatial distribution of the magneticresonance event includes detecting the spatial distribution of themagnetic resonance event associated with one or more ferromagneticmicrostructures selectively-targeted to an antigen epitope. At 1928,detecting the spatial distribution of the magnetic resonance eventincludes detecting the spatial distribution of the magnetic resonanceevent associated with one or more ferromagnetic microstructuresselectively-targeted to an antigen mimotope. At 1930, detecting thespatial distribution of the magnetic resonance event includes detectinga spatial distribution of a magnetic resonance event associated with thetargeted biological sample exposed to a selectively-accessiblesurface-defined void of one or more selectively-targeted,selectively-accessible, ferromagnetic microstructures. At 1932, themethod 1700 includes generating a response based on the detected spatialdistribution of the magnetic resonance event.

At 1934, the method 1700 includes affecting at least one of a non-zerospin nuclei transverse magnetic relaxation time or a non-zero spinnuclei longitudinal magnetic relaxation time associated with abiological sample by providing a plurality of target-specificferromagnetic microstructures to at least a portion of the biologicalsample, at least some of the target-specific ferromagneticmicrostructures including a first internal surface defining a void, thevoid being selectively accessible to the biological sample, thetarget-specific ferromagnetic microstructures including a sufficientamount of at least one ferromagnetic material to generate atime-invariant magnetic field within the void, the time-invariantmagnetic field of a sufficient character to affect at least one of anon-zero spin nuclei transverse magnetic relaxation time or a non-zerospin nuclei longitudinal magnetic relaxation time associated with thebiological sample. At 1936, affecting the at least one of a non-zerospin nuclei transverse magnetic relaxation time or the non-zero spinnuclei longitudinal magnetic relaxation time includes affecting at leastone of a proton transverse magnetic relaxation time or a protonlongitudinal magnetic relaxation time associated with a biologicalsample by providing a plurality of target-specific ferromagneticmicrostructures to at least a portion of the biological sample. At 1938,affecting the at least one of a non-zero spin nuclei transverse magneticrelaxation time or a non-zero spin nuclei longitudinal magneticrelaxation time associated with a biological sample includes providing asufficient amount of a plurality of target-specific ferromagneticmicrostructures including one or more targeting moieties attachedthereof to at least a portion of the biological sample to affecting theat least one of a non-zero spin nuclei transverse magnetic relaxationtime or a non-zero spin nuclei longitudinal magnetic relaxation timeassociated with a biological sample. At 1940, the method 1700 includesdetecting at least one parameter associated with the affected at leastone of a non-zero spin nuclei transverse magnetic relaxation time or anon-zero spin nuclei longitudinal magnetic relaxation time associatedwith the biological sample. At 1942, the method 1700 includes generatinga response based on the detected at least one parameter.

Example 1 Ferromagnetic Microstructures that Target Human Chromosomes Invivo

Ferromagnetic microstructures 102 are constructed with a void 106accessible to biological samples and a static magnetic field within thevoid 106 are targeted to chromosomes in the nucleus of animal cells.Ferromagnetic microstructures 102 that are constructed of iron oxide aremodified by coating with dextran or siloxane and targeting molecules,which promote cellular internalization of the ferromagneticmicrostructures 102, transport to the nucleus, and binding to histonescomprising the chromosomes (see, e.g., U.S. Patent Application No.2008/0206146 (published Aug. 28, 2008, the contents of which isincorporated herein by reference).

Ferromagnetic microstructures 102 configured to target chromosomes areadministered to humans or animals and then are detected in situ bycircuitry systems that detect and report magnetic resonance relaxationprocesses. Chromosome-targeted ferromagnetic microstructures 102 andassociated circuitry systems constitute a nuclear magnetic resonanceimaging system that can image chromosomes, nuclei, cells, and tissues invivo.

Nanoparticles are constructed of iron oxide by adding a solution ofFeCl₃ and FeCl₂ in hydrochloric acid dropwise to a solution of sodiumhydroxide under nitrogen gas at 80° C. The reaction is cooled to roomtemperature and the particles are recovered with an external magnet. Forexample, iron oxide nanoparticles with a diameter of 10±3 nm areproduced. See, e.g., Zhang et al, Cancer Research, vol. 67, pp.1555-1562, (2007) (the contents of which are incorporated herein byreference). Hollow ferromagnetic microstructures 102 with a void 106 arefabricated using colloids as template and electrostatic layer by layerself assembly of inorganic nanoparticles (e.g., Fe₃O₄) and polymermultilayers, followed by removal of the templated core. For example,polystryrene (PS) latex particles 640 nm in diameter are used astemplates and SiO₂ particles (or Fe₃O₄ particles) approximately 25 nm indiameter are used as coating nanoparticles. The nanoparticleselectrostatically self-assemble onto the linear cationic polymer, poly(diallyldimethylammoniumchloride) (PDADMAC, Sigma-Aldrich, St. Louis,Mo.). Repeated cycles layering PDADMAC and SiO₂ results in PS latexcores with multiple layers of PDADMAC and SiO₂ adsorbed. The organicmatter is decomposed by heating to 500° C. and a hollow sphere composedof SiO₂ remains. See, e.g., Caruso et al, Science, vol. 282, 1111-1114(1998) (the contents of which are incorporated herein by reference).Scanning electron microscopy (SEM) and transmission electron microscopy(TEM) are used to characterize the spheres.

In an embodiment, hollow ferromagnetic microstructures 102 aresynthesized in one step by using calcium carbonate CaCO₃ as a removablecore. CaCO₃ nanoparticles (25-60 nm) are combined with Fe₃O₄nanoparticles (5 nm) and tetraethoxysilane under alkaline conditions.The ferromagnetic microstructures 102 are immersed in weak acetic acidto remove the CaCO₃. See, e.g., Wu et al, J. Appl. Physics, vol. 99, pp.08H104-08H104-3 (2006) (the contents of which are incorporated herein byreference). To coat the ferromagnetic microstructures 102, they arecombined with 3-aminopropyltrimethoxy-siloxane (APTMS) after beingtransferred to an organic solvent (e.g., toluene) and then refluxedunder nitrogen gas for 10 hours. Modified ferromagnetic microstructures102 with reactive amino groups are transferred to water andcharacterized (See, e.g., Zhang et al, Ibid.). The APTMS-coatedferromagnetic microstructures 102 are characterized with transmissionelectron microscopy and an image analysis program (for exampleJEOL-100CX transmission electron microscope, JEOL USA, Inc., Peabody,Mass.). Surface charges of the ferromagnetic microstructures 102 aredetermined by measuring the zeta potentials as a function of pH valuesusing a particle charge detector (e.g., PCD 03, Muetec, Herrsching,Germany). Validation of the APTMS coating is determined by energydispersive X-ray analysis and organic elementary analysis (See, e.g.,Zhang et al, Ibid.). A vibrating sample magnetometer (DigitalMeasurement System, Inc., model 155) is employed to measure themagnetization of the ferromagnetic microstructures 102 at roomtemperature. See, e.g., Selim et al, Biomaterials, vol. 28, pp. 710-716(2007) (the contents of which are incorporated herein by reference).Alternatively, the mass magnetization value is determined with a superconducting quantum interference device (SQUID) magnetometer to establishthe electromagnetic units (emu) per gram of magnetic atom. See, e.g.,Lee et al, Nature Medicine, vol. 13, pp. 95-99 (2007) (the contents ofwhich are incorporated herein by reference). Ferromagneticmicrostructures 102 with different magnetic fields are constructed byvarying the metal composition and the size of the iron oxide particles.For example, 12 nm diameter MFe₂O₄ (M═Mn, Fe, Co and Ni) nanoparticlesdisplay different mass magnetization values as measured by a SQUID.Also, the magnetic moments of the MFe₂O₄ nanoparticles vary with theirmetal composition. See Table 1. The mass magnetization of MFe₂O₄nanoparticles is varied by altering the size of the nanoparticles. Forexample, MnFe₂O₄ nanoparticles of 6, 9 and 12 nm diameter displaymagnetization values of 68, 98 and 110 emu/gm respectively (see, e.g.,Lee et al, Ibid.)

TABLE 1 Metal oxide nanoparticles variation in magnetization andmagnetic moment with metal composition (Adapted from Lee et al, Ibid.).Metal Oxide MnFe₂O₄ FeFe₂O₄ CoFe₂O₄ NiFe₂O₄ Mass 110 101 99 85magnetization (emu/g) Magnetic moment 5 μ_(B) 4 μ_(B) 3 μ_(B) 2 μ_(B)

In an embodiment, ferromagnetic microstructures 102 with a void 106 andan opening to allow access of biomolecules (e.g., H₂O) to the void 106and its associated magnetic field are constructed using microfabricationmethods. For example, magnetic microstructures with two disks of metal(e.g., iron) held at a fixed distance by an internal nonmagnetic metalpost or by external biocompatible photo-epoxy posts are fabricated.Microstructures are micromachined through a combination of metalevaporation and electroplating depositions followed by lithographicallydefined ion-milling and selective wet etching. See, e.g., Zabow et al,Nature, vol. 453, pp. 1058-1062 (2008) (the contents of which areincorporated herein by reference). Microfabrication of double diskmicrostructures is scalable and suited to parallel wafer-leveltechniques. Microstructures with diameters between about one mm to about1 μm are constructed, and smaller sub-micrometer structures areconstructed using techniques such as deep-ultraviolet or electron beamlithography. Alternatively, one or more of the microstructures arechemically synthesized. See, e.g., Osaka et al., Chemical Synthesis ofMagnetic nanoparticles and their Applications to Recording Media &Biomedical Materials, 214th ECS Meeting, Abstract No. 2592 (2008) (thecontents of which are incorporated herein by reference).

Targeting molecules are conjugated to the coated ferromagneticmicrostructures 102 (e.g., APTMS-coated) to promote cellularinternalization and to specifically target histone proteins inchromosomes. For example reactive amines present on APTMS-coatedferromagnetic microstructures 102 are derivatized with N-succinimidyl3-(2-pyridyldithio) propionate (SPDP) (Molecular Biosciences, Boulder,Colo.), and a peptide derived from HIV-1 tat protein (amino acids 48-57)is added to the derivatized ferromagnetic microstructures 102 andallowed to react leading to covalent attachment of tat peptide (48-57)to the ferromagnetic microstructures 102. See, e.g., Josephson et al,Bioconjugate Chem., vol. 10, pp. 186-191 (1999) (the contents of whichare incorporated herein by reference). Ferromagnetic microstructures 102conjugated with TAT peptide are efficiently internalized into thecellular cytoplasm and nuclei of mammalian cells. In vitro ferromagneticmicrostructures 102/TAT peptide conjugates are taken up 100-fold moreefficiently than unmodified ferromagnetic microstructures 102 andlymphocytes can take up 1.27×10⁷ particles per cell (Josephson et al,Ibid.)

To target ferromagnetic microstructures 102 to chromosomes, a secondtargeting molecule is attached. Ferromagnetic microstructures 102derivatized with SPDP are reacted with anti-histone antibodies, forexample, anti-histone H3 antibody (Abcam ab1791; Cambridge, Mass.).Derivatized ferromagnetic microstructures 102 are incubated with anequimolar mixture of TAT peptide and anti-histone H3 antibody to attachboth targeting molecules and to promote both cellular internalizationand chromatin binding. Alternatively, anti-histone antibodies can targetmodified histones, such as methylated histones or acetylated histones.For example, antibodies specific for histone H3 methylated at lysine 79(H3K79Me) (Abcam ab3594, Cambridge, Mass.) are used to targetferromagnetic microstructures 102 to chromatin sites that are marked bymodified histones.

Alternatively, a fusion protein comprising TAT peptide and ananti-histone antibody is engineered using recombinant DNA techniques andexpressed in mammalian or microbial expression systems (see, e.g.,Sambrook et al, Molecular Cloning: A Laboratory Manual, 3^(rd) Edition,Cold Spring Harbor Laboratory Press, 2001). The TAT peptide-anti-histoneantibody fusion protein is attached to ferromagnetic microstructures 102derivatized with SPDP as described above (see, also Josephson et al,Ibid.)

Ferromagnetic microstructures 102 with conjugated targeting moleculesare used to image tumor cells in vivo. For example, Fe₃O₄ ferromagneticmicrostructures 102 with an anti-HER2 (human epidermal growth factorreceptor-2) antibody (e.g., Herceptin, Genentech, South San Francisco,Calif.) conjugated to their surface are injected intravenously into nudemice bearing tumors expressing HER2 (e.g., NIH3T6.7) the ferromagneticmicrostructures 102 are detected via radio frequency (RF) coils (e.g.,surface coils, bird cage coils, or volume coils; available from BrukerBioSpin Corp., Billerica, Mass.).

For example, magnetic nanoparticles with targeting molecules attached,(e.g., Herceptin) are injected intravenously in tumor bearing animalsand detected 2 hours later using a 1.5-T clinical MRI instrument with amicro-47 surface coil (Intera; Philips Medical Systems). Using optimizedferromagnetic microstructures 102 with an accessible void 106 it may bepossible to detect small tumors in vivo that weigh approximately 50 mg(Lee et al, Ibid.).

To image a region within a biological subject, in vivo, and in theabsence of external magnetic fields, ferromagnetic microstructures 102with voids 106 and known magnetic fields (e.g., magnetic moments) arepulsed with radiowaves at the Larmor frequency for the non-zero spinnuclei of interest in a magnetic field as determined by the equation:ω_(L)=γH where ω_(L) is the Larmor frequency and γ is the gyromagneticratio for the non-zero spin nuclei of interest and H is the magneticfield strength. Absorption of radiowaves at ω_(L) by the non-zero spinnuclei in the void 106 leads to higher energy state transitions andsubsequent emission of radiowaves following stoppage of the radiowavepulse. The relaxation or radiowave emission is characterized by a timeconstant, T₂ that depends on the molecular environment of the non-zerospin nuclei in the magnetic field of the void 106. Radiowaves emitted atthe Larmor frequency induce currents in receiver RF coils and theinduced currents are amplified by RF preamplifiers and then transmittedto a receiver unit responsible for digitizing and storing the data priorto transfer to a host computer. See, e.g., Silva et al, Concepts inMagnetic. Resonance Part A, vol. 16A, pp. 35-49 (2003) (the contents ofwhich are incorporated herein by reference). Hardware andinstrumentation for magnetic resonance imaging are available at BrukerBioSpin, Corp., Billerica, Mass. Moreover, by tuning the ferromagneticmicrostructures 102 magnetic field strength and the correspondingreceiver RF coil resonance frequency it is possible to specificallydetect different ferromagnetic microstructures 102 in multiplex. Forexample, ferromagnetic microstructures 102 with different magneticmoments of 5 μ_(B) and 2 μ_(B) are detected via RF coils that differ intheir resonance frequency by a factor of 2.5. Thus, controlferromagnetic microstructures 102, without targeting molecules attachedcan be detected simultaneously with targeted ferromagneticmicrostructures 102 by using distinct ferromagnetic microstructures 102and RF coils with different magnetic field strengths and resonancefrequencies respectively.

Example 2 Ferromagnetic Microstructures for Magnetic Resonance Imagingof Beta-Amyloid Plaque

Ferromagnetic microstructures 102 can be targeted to aggregated betaamyloid associated with Alzheimer's disease and they can be used fornoninvasive detection of beta amyloid plaques. Conjugation of peptides,antibodies or small molecules to the surface of derivatizedferromagnetic microstructures 102 can mediate specific binding andlocalization of the ferromagnetic microstructures 102 to aggregated betaamyloid and beta amyloid plaques. In addition, coating or conjugation ofapolipoproteins, peptides, small molecules, and surfactants to theferromagnetic microstructures 102 surface can promote their transit ofthe blood brain barrier (BBB). See, e.g., Fenart et al., Evaluation ofEffect of Charge and Lipid Coating on Ability of 60-nm Nanoparticles toCross an In Vitro Model of the Blood-Brain Barrier, 291(3): 1017-1022,(1999) (the contents of which are incorporated herein by reference).

Ferromagnetic microstructures 102 modified to promote transit of the BBBare administered intravenously or intra-arterially to detect betaamyloid plaque in the brain. Modified ferromagnetic microstructures 102with a void 106 and localized to beta amyloid plaque are detected bymagnetic resonance imaging without the need for a strong externalmagnetic field. Thus, ferromagnetic microstructures 102 targeted to betaamyloid plaque can represent a relatively low cost, noninvasive methodto detect beta amyloid plaque and to help diagnose Alzheimer's disease.

Ferromagnetic microstructures 102 containing an accessible void 106 aremodified by coating or conjugation of proteins and surfactants topromote transit across the BBB. For example, coupling apolipoprotein Eto the surface of nanoparticles via an avidin/biotin linkage can promotetransit across the BBB. See, e.g., Michaelis et al, Journal Pharmacologyand Experimental Therapeutics, vol. 317, pp. 1246-1253 (2006) (thecontents of which are incorporated herein by reference).

Iron oxide ferromagnetic microstructures 102 are coated with APTMS, asiloxane with functional amino groups, using methods detailed in Zhanget al, Ibid. APTMS-coated ferromagnetic microstructures 102 can then bereacted with a polyethylene glycol crosslinker, NHS-PEG3400-Mal (Nektar,Huntsville, Ala.) to derive sulfhydryl-reactive ferromagneticmicrostructures 102. Avidin (NeutrAvidin, Pierce, Rockford, Ill.) isderivatized with 2-iminothiolane/HCL (Pierce, Rockford, Ill.) to createavidin with sulfhydryl groups which are combined with thesulfhydryl-reactive ferromagnetic microstructures 102 to yieldferromagnetic microstructures 102 with avidin on their surface.Apolipoprotein E (recombinant human apolipoprotein E3; LeincoTechnologies, Inc., St. Louis, Mo.) is biotinylated using standardprotocols accompanying biotinylation reagents (PFP-Biotin, Pierce,Rockford, Ill.) and then added to avidin-coupled ferromagneticmicrostructures 102 to create ferromagnetic microstructures 102 withapolipoprotein E on their surface (Michaelis et al, Ibid.).Alternatively, ferromagnetic microstructures 102 are coated withsurfactants to promote transit across the BBB. For example, coatingferromagnetic microstructures 102 with polysorbate 80 (MallinckrodtBaker, Inc., Phillipsburg, N.J. 08865) using described methods (see,e.g., Michaelis et al, Ibid.) may promote their transport across theBBB.

To target ferromagnetic microstructures 102 for beta amyloid plaques,peptides, antibodies or small molecules with affinity for beta amyloidaggregates are attached to the surface of the ferromagneticmicrostructures 102. For example, a peptide, Aβ1-40, derived fromamyloid precursor protein (APP) binds with high affinity to beta amyloidplaques and can be used to target ferromagnetic microstructures 102 tobeta amyloid plaque. See, e.g., Wadghiri et al, Magnetic ResonanceMedicine, vol. 50, pp. 293-302 (2003) (the contents of which areincorporated herein by reference). Ferromagnetic microstructures 102 arecoated with dextran and then Aβ1-40 peptide is adsorbed onto theferromagnetic microstructures 102 using standard methods (see, e.g.,Wadghiri et Ibid.). To deliver Aβ1-40-ferromagnetic microstructures 102to brain tissues in animals (e.g., transgenic mice overexpressing APP)they are co-injected into the carotid artery with mannitol (to promotetransit across the BBB) as described (see, e.g., Wadghiri et al, Ibid.).Alternatively, ferromagnetic microstructures 102 with avidin covalentlycoupled on their surface may be mixed with an equimolar mixture ofbiotinylated Aβ1-40 and biotinylated apolipoprotein E (see, e.g.,Michaelis et al, Ibid.) to produce ferromagnetic microstructures 102suitable for injection in the carotid artery that may cross the BBB anddistribute in the brain.

One can detect ferromagnetic microstructures 102 localized to betaamyloid plaques in animal brains ex vivo by magnetic resonance imaging,histochemistry and immunohistochemistry. For example ex vivo magneticresonance imaging of fixed whole mouse brains following intra-arterialinjection of magnetic Aβ1-40-nanoparticles is done using a SMIS consoleinterfaced to a 7 Tesla horizontal bore magnet equipped with 250 mT/mactively shielded gradients (Magnex Scientific, Abdingdon, UK). Magneticresonance imaging methods using T₂-weighted spin echo pulsing canaccurately detect beta amyloid plaque numerical density in correlationwith immunohistochemistry techniques (see, e.g., Wadghiri et al, Ibid.).

At least a portion of the devices and/or processes described herein canbe integrated into a data processing system. A data processing systemgenerally includes one or more of a system unit housing, a video displaydevice, memory such as volatile or non-volatile memory, processors suchas microprocessors or digital signal processors, computational entitiessuch as operating systems, drivers, graphical user interfaces, andapplications programs, one or more interaction devices (e.g., a touchpad, a touch screen, an antenna, etc.), and/or control systems includingfeedback loops and control motors (e.g., feedback for sensing positionand/or velocity, control motors for moving and/or adjusting componentsand/or quantities). A data processing system may be implementedutilizing suitable commercially available components, such as thosetypically found in data computing/communication and/or networkcomputing/communication systems.

The herein described subject matter sometimes illustrates differentcomponents contained within, or connected with, different othercomponents. It is to be understood that such depicted architectures aremerely examples, and that in fact, many other architectures may beimplemented that achieve the same functionality. In a conceptual sense,any arrangement of components to achieve the same functionality iseffectively “associated” such that the desired functionality isachieved. Hence, any two components herein combined to achieve aparticular functionality can be seen as “associated with” each othersuch that the desired functionality is achieved, irrespective ofarchitectures or intermedial components. Likewise, any two components soassociated can also be viewed as being “operably connected”, or“operably coupled,” to each other to achieve the desired functionality,and any two components capable of being so associated can also be viewedas being “operably coupleable,” to each other to achieve the desiredfunctionality. Specific examples of operably coupleable include, but arenot limited to, physically mateable and/or physically interactingcomponents, and/or wirelessly interactable, and/or wirelesslyinteracting components, and/or logically interacting, and/or logicallyinteractable components.

In an embodiment, one or more components may be referred to herein as“configured to,” “configurable to,” “operable/operative to,”“adapted/adaptable,” “able to,” “conformable/conformed to,” etc. Suchterms (e.g., “configured to”) can generally encompass active-statecomponents and/or inactive-state components and/or standby-statecomponents, unless context requires otherwise.

The foregoing detailed description has set forth various embodiments ofthe devices and/or processes via the use of block diagrams, flowcharts,and/or examples. Insofar as such block diagrams, flowcharts, and/orexamples contain one or more functions and/or operations, it will beunderstood by the reader that each function and/or operation within suchblock diagrams, flowcharts, or examples can be implemented, individuallyand/or collectively, by a wide range of hardware, software, firmware, orvirtually any combination thereof. Further, the use of “Start,” “End” or“Stop” blocks in the block diagrams is not intended to indicate alimitation on the beginning or end of any functions in the diagram. Suchflowcharts or diagrams may be incorporated into other flowcharts ordiagrams where additional functions are performed before or after thefunctions shown in the diagrams of this application. In an embodiment,several portions of the subject matter described herein may beimplemented via Application Specific Integrated Circuits (ASICs), FieldProgrammable Gate Arrays (FPGAs), digital signal processors (DSPs), orother integrated formats. However, some aspects of the embodimentsdisclosed herein, in whole or in part, can be equivalently implementedin integrated circuits, as one or more computer programs running on oneor more computers (e.g., as one or more programs running on one or morecomputer systems), as one or more programs running on one or moreprocessors (e.g., as one or more programs running on one or moremicroprocessors), as firmware, or as virtually any combination thereof,and that designing the circuitry and/or writing the code for thesoftware and or firmware would be well within the skill of one of skillin the art in light of this disclosure. In addition, the mechanisms ofthe subject matter described herein are capable of being distributed asa program product in a variety of forms, and that an illustrativeembodiment of the subject matter described herein applies regardless ofthe particular type of signal-bearing medium used to actually carry outthe distribution. Examples of a signal-bearing medium include, but arenot limited to, the following: a recordable type medium such as a floppydisk, a hard disk drive, a Compact Disc (CD), a Digital Video Disk(DVD), a digital tape, a computer memory, etc.; and a transmission typemedium such as a digital and/or an analog communication medium (e.g., afiber optic cable, a waveguide, a wired communications link, a wirelesscommunication link (e.g., transmitter, receiver, transmission logic,reception logic, etc.), etc.).

While particular aspects of the present subject matter described hereinhave been shown and described, it will be apparent to the reader that,based upon the teachings herein, changes and modifications may be madewithout departing from the subject matter described herein and itsbroader aspects and, therefore, the appended claims are to encompasswithin their scope all such changes and modifications as are within thetrue spirit and scope of the subject matter described herein. Ingeneral, terms used herein, and especially in the appended claims (e.g.,bodies of the appended claims) are generally intended as “open” terms(e.g., the term “including” should be interpreted as “including but notlimited to,” the term “having” should be interpreted as “having atleast,” the term “includes” should be interpreted as “includes but isnot limited to,” etc.). Further, if a specific number of an introducedclaim recitation is intended, such an intent will be explicitly recitedin the claim, and in the absence of such recitation no such intent ispresent. For example, as an aid to understanding, the following appendedclaims may contain usage of the introductory phrases “at least one” and“one or more” to introduce claim recitations. However, the use of suchphrases should not be construed to imply that the introduction of aclaim recitation by the indefinite articles “a” or “an” limits anyparticular claim containing such introduced claim recitation to claimscontaining only one such recitation, even when the same claim includesthe introductory phrases “one or more” or “at least one” and indefinitearticles such as “a” or “an” (e.g., “a” and/or “an” should typically beinterpreted to mean “at least one” or “one or more”); the same holdstrue for the use of definite articles used to introduce claimrecitations. In addition, even if a specific number of an introducedclaim recitation is explicitly recited, such recitation should typicallybe interpreted to mean at least the recited number (e.g., the barerecitation of “two recitations,” without other modifiers, typicallymeans at least two recitations, or two or more recitations).Furthermore, in those instances where a convention analogous to “atleast one of A, B, and C, etc.” is used, in general such a constructionis intended in the sense of the convention (e.g., “a system having atleast one of A, B, and C” would include but not be limited to systemsthat have A alone, B alone, C alone, A and B together, A and C together,B and C together, and/or A, B, and C together, etc.). In those instanceswhere a convention analogous to “at least one of A, B, or C, etc.” isused, in general such a construction is intended in the sense of theconvention (e.g., “a system having at least one of A, B, or C” wouldinclude but not be limited to systems that have A alone, B alone, Calone, A and B together, A and C together, B and C together, and/or A,B, and C together, etc.). Typically a disjunctive word and/or phrasepresenting two or more alternative terms, whether in the description,claims, or drawings, should be understood to contemplate thepossibilities of including one of the terms, either of the terms, orboth terms unless context dictates otherwise. For example, the phrase “Aor B” will be typically understood to include the possibilities of “A”or “B” or “A and B.”

With respect to the appended claims, the operations recited thereingenerally may be performed in any order. Also, although variousoperational flows are presented in a sequence(s), it should beunderstood that the various operations may be performed in orders otherthan those that are illustrated, or may be performed concurrently.Examples of such alternate orderings may include overlapping,interleaved, interrupted, reordered, incremental, preparatory,supplemental, simultaneous, reverse, or other variant orderings, unlesscontext dictates otherwise. Furthermore, terms like “responsive to,”“related to,” or other past-tense adjectives are generally not intendedto exclude such variants, unless context dictates otherwise.

While various aspects and embodiments have been disclosed herein, otheraspects and embodiments are contemplated. The various aspects andembodiments disclosed herein are for purposes of illustration and arenot intended to be limiting, with the true scope and spirit beingindicated by the following claims.

1. A multiplex nuclear magnetic resonance imaging composition,comprising a plurality of ferromagnetic microstructure sets, eachferromagnetic microstructure set comprising one or more ferromagneticmicrostructures configured to include an accessible internal void andconfigured to generate a characteristic time-invariant magnetic fieldwithin the accessible internal void; and at least one of theferromagnetic microstructure sets having a different characteristictime-invariant magnetic field from another of the plurality offerromagnetic microstructure sets.
 2. The composition of claim 1,wherein each ferromagnetic microstructure set comprises a differentcharacteristic time-invariant magnetic field magnitude.
 3. Thecomposition of claim 1, wherein each ferromagnetic microstructure setcomprises a different characteristic magnetic field spatialdistribution.
 4. The composition of claim 1, wherein the plurality offerromagnetic microstructure sets include at least a first ferromagneticmicrostructure set including one or more ferromagnetic microstructuresconfigured to generate a first magnetic field spatial distributionwithin an accessible internal void and a second ferromagneticmicrostructure set including one or more ferromagnetic microstructuresconfigured to generate a second magnetic field spatial distributionwithin an accessible internal void, the second magnetic field spatialdistribution having a different spatial distribution from the firstmagnetic field spatial distribution.
 5. The composition of claim 1,wherein each ferromagnetic microstructure set comprises a differentaccessible internal void dimension.
 6. The composition of claim 1,wherein each ferromagnetic microstructure set comprises a differentnumber of accessible internal voids.
 7. The composition of claim 1,wherein each ferromagnetic microstructure set comprises a differentferromagnetic material.
 8. The composition of claim 1, wherein eachferromagnetic microstructure set comprises a different ferromagneticmaterial.
 9. The composition of claim 1, wherein each ferromagneticmicrostructure set is configured to affect at least one of an in vivoproton transverse magnetic relaxation time or an in vivo protonlongitudinal magnetic relaxation time.
 10. The composition of claim 1,wherein one or more of the ferromagnetic microstructure sets areconfigured to allow an in vivo biological sample selective-access to theinternal void.
 11. The composition of claim 1, wherein one or more ofthe ferromagnetic microstructure sets include an ion-selectiveselectively-accessible internal void.
 12. The composition of claim 1,wherein one or more of the ferromagnetic microstructure sets include amolecule-selective selectively-accessible internal void.
 13. Thecomposition of claim 1, wherein one or more of the ferromagneticmicrostructure sets include one or more ferromagnetic microstructuresincluding one or more bound targeting moieties.
 14. A multiplex imagingmethod, comprising affecting at least one of a proton transversemagnetic relaxation time or a proton longitudinal magnetic relaxationtime associated with a biological sample by providing a plurality offerromagnetic microstructure sets, each ferromagnetic microstructure setcomprising one or more ferromagnetic microstructures configured toinclude an accessible internal void and configured to generate acharacteristic time-invariant magnetic field within the accessibleinternal void; and one or more of the ferromagnetic microstructure setshaving a different characteristic time-invariant magnetic field.
 15. Themethod of claim 14, further comprising: detecting at least one parameterassociated with the affected at least one of a proton transversemagnetic relaxation time or a proton longitudinal magnetic relaxationtime associated with the biological sample.
 16. The method of claim 14,further comprising: generating a response based on the detected at leastone parameter.
 17. A method of multiplex interrogation of a biologicalsample, comprising: detecting nuclear magnetic resonance informationgenerated by in vivo nuclear magnetic resonance detectable nucleiexposed to one or more internal-surface-defined voids of a plurality ofdifferent ferromagnetic microstructures configured to generate a staticmagnetic flux density within at least a portion of the one or moreinternal-surface-defined voids and configured to affect a magneticresonance relaxation process associated with the in vivo nuclearmagnetic resonance detectable nuclei while the in vivo nuclear magneticresonance detectable nuclei are received in at least one of the one ormore internal-surface-defined voids.
 18. The method of claim 17, whereindetecting the nuclear magnetic resonance information generated by invivo nuclear magnetic resonance detectable nuclei exposed to one or moreinternal-surface-defined voids of a plurality of different ferromagneticmicrostructures includes detecting nuclear magnetic resonanceinformation generated by in vivo nuclear magnetic resonance detectablenuclei exposed to one or more internal-surface-defined voids of aplurality of different ferromagnetic microstructures having two or moredifferent characteristic time-invariant magnetic fields.
 19. The methodof claim 17, wherein detecting the nuclear magnetic resonanceinformation generated by in vivo nuclear magnetic resonance detectablenuclei exposed to one or more internal-surface-defined voids of aplurality of different ferromagnetic microstructures includes detectingnuclear magnetic resonance information generated by in vivo nuclearmagnetic resonance detectable nuclei exposed to one or moreinternal-surface-defined voids of a plurality of different ferromagneticmicrostructures having two or more different static magnetic fluxdensities.
 20. The method of claim 17, wherein detecting the nuclearmagnetic resonance information generated by in vivo nuclear magneticresonance detectable nuclei exposed to one or moreinternal-surface-defined voids of a plurality of different ferromagneticmicrostructures includes detecting nuclear magnetic resonanceinformation generated by in vivo nuclear magnetic resonance detectablenuclei exposed to one or more internal-surface-defined voids of aplurality of different ferromagnetic microstructures linked to one ormore different targeting moieties.